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The Scientific World Journal
Volume 2012 (2012), Article ID 491737, 13 pages
http://dx.doi.org/10.1100/2012/491737
Review Article

Cell Cycle Inhibition without Disruption of Neurogenesis Is a Strategy for Treatment of Aberrant Cell Cycle Diseases: An Update

Department of Neurology and the MIND Institute, University of California at Davis, Sacramento, CA 95817, USA

Received 13 October 2011; Accepted 17 November 2011

Academic Editors: F. Bareyre and B. K. Jin

Copyright © 2012 Da-Zhi Liu and Bradley P. Ander. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Since publishing our earlier report describing a strategy for the treatment of central nervous system (CNS) diseases by inhibiting the cell cycle and without disrupting neurogenesis (Liu et al. 2010), we now update and extend this strategy to applications in the treatment of cancers as well. Here, we put forth the concept of “aberrant cell cycle diseases” to include both cancer and CNS diseases, the two unrelated disease types on the surface, by focusing on a common mechanism in each aberrant cell cycle reentry. In this paper, we also summarize the pharmacological approaches that interfere with classical cell cycle molecules and mitogenic pathways to block the cell cycle of tumor cells (in treatment of cancer) as well as to block the cell cycle of neurons (in treatment of CNS diseases). Since cell cycle inhibition can also block proliferation of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits, we propose that future strategies aimed at cell cycle inhibition in treatment of aberrant cell cycle diseases (i.e., cancers or CNS diseases) should be designed with consideration of the important side effects on normal neurogenesis and cognition.

1. Introduction

The cell cycle is an irreversible, ordered set of events that normally leads to cellular division [15]. The release of cells from a quiescent state (G0) results in their entry into the first gap phase (G1), during which the cells prepare for DNA replication in the synthetic phase (S). This is followed by the second gap phase (G2) and mitosis phase (M). After the cell has split into its two daughter cells, the new cells enter either G1 or G0. Tumors usually originate from adult tissues, in which the majority of cells are in the G0 quiescent phase [4]. Mature neurons normally maintain themselves in G0 resting phase. These facts suggest that the cells that go on to form tumors and mature neurons share a common G0 state of quiescence.

Since cell cycle is irreversible, this raises a possibility that irreversible cell cycle reentry mediates the irreversible neuronal death that mirrors the irreversible progression of some central nervous system (CNS) diseases, such as Alzheimer’s disease (AD). If this is true, it will partially explain why AD is incurable once even early AD symptoms occur, for the early AD symptoms may indicate that the neurons have reentered the cell cycle that ends up leading to neuronal death and AD progression. Thus, the best strategy in treatment of CNS diseases is to prevent cell cycle re-entry at the early stage before neurons leave the G0 phase at all, since even the mere entrance into the initial cell cycle may lead to unavoidable neuronal death.

Since re-entry into the cell cycle by tumor cells or neurons has been associated with many tumor or CNS diseases and linked to uncontrolled cell proliferation (in cancer) or neuronal death (in CNS diseases), cell cycle inhibition strategies are of interest in the treatment of both tumor and CNS diseases. For instance, the cell cycle inhibitors, such as cyclin-dependent kinase (CDK) inhibitors, have been widely studied as cancer therapeutics. They have been used to inhibit growth of several types of tumor cells in numerous preclinical studies, both in vitro and in vivo [612]. Several cell cycle inhibitors have advanced to human clinical trials for evaluation as a treatment for a broad range of solid tumors and hematological malignancies such as chronic lymphocytic leukemia (CLL) [1317]. Though no clinical trials of the cell cycle inhibitors are reported in the treatment of CNS diseases, preclinical experiments demonstrate that the cell cycle inhibitors improve behavioral outcomes and increase neuronal survival in a series of CNS disease models [1833].

Cell cycle inhibition kills tumor cells (in treatment of cancer) or protects mature neurons from death (in treatment of CNS diseases), whereas this can also block proliferation of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits in the patients of cancer and CNS diseases [1]. Since the presence of cognitive deficits is a major factor markedly affecting quality of life of these patients, the cell cycle inhibition strategy in treatment of cancer and CNS diseases should consider the consequences on other cell types that can be affected, such as NPCs.

As a way to describe the two seemingly different disease types (i.e., cancer and CNS diseases) that share the common mechanism of cell cycle re-entry, we propose a broader term of “aberrant cell cycle diseases”—one which includes not only cancers but also CNS diseases. A detailed description of how the cell cycle re-entry, at least in part, underlies cancers and CNS diseases follows before we discuss the pharmacological approaches that have been examined in therapeutic treatment of the two disease types.

2. Aberrant Cell Cycle Diseases: Cancers and CNS Diseases

Cancers and CNS diseases are two major threats to human health. Epidemiological studies show that patients with CNS disease, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and multiple sclerosis (MS), have a significantly lower risk of most cancers [3438]. The reverse correlations also hold true: cancer survivors have a significantly lower risk of developing some of these CNS diseases. However, there are exceptions: Parkinson’s patients have an increased risk for melanoma [3944], autism patients have an increased risk for breast cancer [45], and Fragile X Syndrome patients have increased risk for lip cancer [46]. No matter what associations underlie certain cancers and CNS diseases, these correlative studies have raised an interesting question: what associated processes or mechanisms do dying neurons and growing tumor cells have in common?

Aberrant cell cycle is the hallmark of many tumor cells in cancers [4749] and is also observed in postmortem and/or animal studies of dying neurons in a series of CNS diseases, such as AD, PD, stroke, epilepsy, cerebral hypoxia-ischemia, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), among others [1833, 5064]. Although tumor cells undergo uncontrolled proliferation, many tumors originate from adult tissues in which the majority of cells are in the G0 quiescent phase [4]. Similarly, mature neurons stay in G0 quiescent phase in normal physiological conditions, but do reenter the cell cycle irregularly (and die) in certain pathological conditions.

Thus, the cells that go on to form tumors and healthy neurons share a common G0 state of quiescence. However, if tumor cells re-enter the cell cycle, they survive and often proliferate, whereas mature neurons will die. Therefore, cell cycle inhibition can be applied not only to kill tumor cells (in treatment of cancer), but also to protect neurons from death (in treatment of CNS diseases). This is strongly supported by the findings that mutation of PARK2, a tumor suppressor gene, results not only in neuronal death in Parkinson’s disease, but also in tumor cell proliferation in glioblastoma and other human cancer [65]. Consistently, cell cycle inhibition mot only promotes the death of naive PC12 (pheochromocytoma) tumor cells, but also prevents the death of nerve growth factor- (NGF-) differentiated PC12 neuronal cells [66, 67].

3. Cell Cycle and “Expanded Cell Cycle”

Classically, the proteins and regulators of the cell cycle include CDKs, cyclins, CDK inhibitors, and CDK substrates. However, the cell cycle inhibition strategies that target on these molecules lack specificity for their target tumor cells or dying neurons and thus interfere the normal biological processes performed by other cell types, since the core cell-cycle-associated molecules are often highly conserved throughout eukaryotes, thus we proposed an “expanded cell cycle” to include not only the core cell cycle molecules mentioned above, but also the mitogenic molecules and the signaling pathways that interact with them. Under specific environmental and/or pathological conditions, such as exposure of tobacco smoke, benzene, ultraviolet B radiation, and/or enhancement of mitogenic molecules (i.e., thrombin, growth factors, amyloid beta, etc.), activation of specific pathways to mediate abnormal cell cycle re-entry may arise and thus trigger tumorigenesis of normal cells and/or death of neurons. It is always impossible to prove exactly what caused a cancer or CNS disease in any individual, because most of these diseases have multivariate causes. However, the various causes seem to result in a common outcome—cell cycle re-entry, mediated by several common mitogenic pathways. The main mitogenic pathways include (1) FAK/Src/Ras/Raf/MEK1, 2/ERK1, 2 → cell cycle re-entry [6872]; (2) Ras/Rac1/MEK3, 6/P38 → cell cycle re-entry [73, 74]; (3) PLC/IP3/PKC/JNK → cell cycle re-entry [75, 76]; (4) PI3K/Akt/mTOR/Tau → cell cycle re-entry [60, 77, 78]; (5) JAK/STAT → cell cycle re-entry [79, 80]. In addition, many molecules, including ROS, PGE2, NO, and Ca2+, can directly or indirectly participate in the main mitogenic signaling pathways [8186]. The idea of an “expanded cell cycle” provides a wider view encompassing a broad range of molecules representing potential targets and thus approaches that can serve as treatments for cancer and CNS diseases—all sharing the common outcome of cell cycle inhibition.

4. Pharmacological Approaches Interfering with the “Expanded Cell Cycle” in Treatment of Aberrant Cell Cycle Diseases

In theory any part of the “expanded cell cycle” could act as a potential target for drug discovery. For example, thrombin activation is substantially increased in cancers [8789] and CNS diseases (i.e., AD, stroke). Thrombin may then go on to activate Src kinases [90, 91]. Src kinases will activate MAPK which will activate CDK4/cyclinD complexes and promote cell cycle re-entry [71, 91, 92]. Thus, these molecules (thrombin, Src kinases, and MAPK), while not considered traditional components of the cell cycle, would all be considered part of the “expanded cell cycle.” Similarly, other protein kinases (including JAK, Akt, PKC, JNK, ERK, GSK-3β.) are also important molecules in the mitogenic pathways leading to neuronal cell cycle re-entry. Most targets mentioned above have been examined in cancer therapies as well as in CNS diseases. Pharmacological approaches based on those targets include traditional cell cycle inhibitors (CDK inhibitors), antioxidants, NMDA-receptor modulators, i/eNOS inhibitors, COX-2 inhibitors, protein kinase inhibitors, and others (Table 1).

tab1
Table 1: Pharmacological approaches interfering with mitogenic molecules and signaling pathways of the “expanded cell cycle” in treatments of cancer and CNS diseases.

5. Cognitive Side Effects of Clinic Therapies for Aberrant Cell Cycle Diseases

In treatment of peripheral or brain cancers, surgical removal of the tumor is recommended whenever possible. Anticancer medications (chemotherapy, CT) may be prescribed, as well as radiation therapy (RT). CT- or RT is cytotoxic, not only slowing down or killing rapidly dividing cells and producing many different types of DNA damage [93], but detrimentally leading to damage of normal tissue, especially of fast-growing healthy cells, including neural progenitor cells (NPCs), and also red and white blood cells [94, 95]. Recent reports show that CT results in cognitive side effects in extracranial cancer (i.e., breast cancer, prostate, etc.) patients [9698], and CT or RT has also been associated with neurogenesis impairment and long-term cognitive deficits in brain cancer patients [99105]. The main idea that is thought to contribute to the CT or RT-induced cognitive decline is that these treatments block proliferation of NPCs in the hippocampal and periventricular zones, which cannot be repopulated as healthy cells die. This leads to cognitive decline, since the NPCs help maintain neurogenesis [106109], repair damage from brain injury [105, 109118], and are important in cognition [119121].

Besides the CT and RT mentioned above in treatment of cancers, some pharmacological approaches that interfere with classical cell cycle molecules or mitogenic pathways have been examined in cancer and CNS disease therapies (Table 1). Therapies directed at any component inhibiting the cell cycle must be as specific as possible considering cell cycle re-entry contributes to the proliferation of tumor cells, the death of mature neurons, and the genesis of NPCs in adult brain. Therefore, any therapeutics that prevent tumor growth and/or neuronal death by blocking cell cycle re-entry may have limited benefit because they may impair neurogenesis and thus lead to cognitive side effects. This may provide at least a partial explanation for the questionable efficacy of some currently approved drugs, such as the NMDA receptor modulator Memantine, in the clinical treatment of AD [122], since NMDA receptor inhibition has been shown to block progenitor cell proliferation and lead to impaired neurogenesis [123].

The cognitive side effects may be explained by the fact that current cell cycle inhibition strategies are not cell specific and also block the proliferation of important brain progenitor cells, thus impairing adult brain neurogenesis. If drugs that block the cell cycle are used to kill tumor cells (in treatment of cancer) and/or help protect neurons (in treatment of CNS diseases), it is likely that compounds would need to directly (or indirectly) block tumor and neuronal cell cycle re-entry and yet not affect the ongoing process of neurogenesis. This will only be possible if the signaling mechanisms are different in NPCs that divide in the adult brain, versus tumor cells and neurons that re-enter the cell cycle irregularly.

6. Conclusions

Cancer and CNS diseases, two seemingly different disease types, at least in part share the common molecular pathology of cell cycle re-entry. With this knowledge in mind, novel insights into cell cycle inhibition strategies to be used in treatment of the “aberrant cell cycle diseases” may be made. Future studies aimed at better understanding the respective cell cycle pathways of tumor cells, neurons, and NPCs are probably necessary before choosing the best drug targets for treating certain “aberrant cell cycle diseases” so as to consider the most effective benefits to the patient without causing indirect harm in related, but different systems.

Acknowledgment

The authors acknowledge the support of the University of California Innovative Development Award (D. Z. Liu).

References

  1. D. Z. Liu, B. P. Ander, and F. R. Sharp, “Cell cycle inhibition without disruption of neurogenesis is a strategy for treatment of central nervous system diseases,” Neurobiology of Disease, vol. 37, no. 3, pp. 549–557, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. B. Novak, J. J. Tyson, B. Gyorffy, and A. Csikasz-Nagy, “Irreversible cell-cycle transitions are due to systems-level feedback,” Nature Cell Biology, vol. 9, no. 7, pp. 724–728, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. C. Norbury and P. Nurse, “Animal cell cycles and their control,” Annual Review of Biochemistry, vol. 61, pp. 441–470, 1992. View at Scopus
  4. M. Malumbres and M. Barbacid, “To cycle or not to cycle: a critical decision in cancer,” Nature Reviews Cancer, vol. 1, no. 3, pp. 222–231, 2001. View at Scopus
  5. G. K. Schwartz and M. A. Shah, “Targeting the cell cycle: a new approach to cancer therapy,” Journal of Clinical Oncology, vol. 23, no. 36, pp. 9408–9421, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. S. Erickson, O. Sangfelt, M. Heyman, J. Castro, S. Einhorn, and D. Grandér, “Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence,” Oncogene, vol. 17, no. 5, pp. 595–602, 1998. View at Scopus
  7. G. I. Shapiro, D. A. Koestner, C. B. Matranga, and B. J. Rollins, “Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines,” Clinical Cancer Research, vol. 5, no. 10, pp. 2925–2938, 1999. View at Scopus
  8. M. Chien, M. Astumian, D. Liebowitz, C. Rinker-Schaeffer, and W. M. Stadler, “In vitro evaluation of flavopiridol, a novel cell cycle inhibitor, in bladder cancer,” Cancer Chemotherapy and Pharmacology, vol. 44, no. 1, pp. 81–87, 1999. View at Publisher · View at Google Scholar · View at Scopus
  9. G. K. Schwartz, K. Farsi, P. Maslak, D. P. Kelsen, and D. Spriggs, “Potentiation of apoptosis by flavopiridol in mitomycin-C-treated gastric and breast cancer cells,” Clinical Cancer Research, vol. 3, no. 9, pp. 1467–1472, 1997. View at Scopus
  10. F. Arguello, M. Alexander, J. A. Sterry et al., “Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts,” Blood, vol. 91, no. 7, pp. 2482–2490, 1998. View at Scopus
  11. M. Drees, W. A. Dengler, T. Roth et al., “Flavopiridol (L86-8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells,” Clinical Cancer Research, vol. 3, no. 2, pp. 273–279, 1997. View at Scopus
  12. O. M. Tirado, S. Mateo-Lozano, and V. Notario, “Roscovitine is an effective inducer of apoptosis of Ewing's sarcoma family tumor cells in vitro and in vivo,” Cancer Research, vol. 65, no. 20, pp. 9320–9327, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. P. G. Wyatt, A. J. Woodhead, V. Berdini et al., “Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H- pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design,” Journal of Medicinal Chemistry, vol. 51, no. 16, pp. 4986–4999, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. A. M. Senderowicz, “Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials,” Investigational New Drugs, vol. 17, no. 3, pp. 313–320, 1999. View at Publisher · View at Google Scholar · View at Scopus
  15. S. R. Whittaker, R. H. Te Poele, F. Chan et al., “The cyclin-dependent kinase inhibitor seliciclib (R-roscovitine; CYC202) decreases the expression of mitotic control genes and prevents entry into mitosis,” Cell Cycle, vol. 6, no. 24, pp. 3114–3131, 2007. View at Scopus
  16. A. M. Senderowicz and E. A. Sausville, “Preclinical and clinical development of cyclin-dependent kinase modulators,” Journal of the National Cancer Institute, vol. 92, no. 5, pp. 376–387, 2000. View at Scopus
  17. M. A. Dickson and G. K. Schwartz, “Development of cell-cycle inhibitors for cancer therapy,” Current Oncology, vol. 16, no. 2, pp. 36–43, 2009. View at Scopus
  18. A. Copani, D. Ubertia, M. A. Sortino, V. Bruno, F. Nicoletti, and M. Memo, “Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?” Trends in Neurosciences, vol. 24, no. 1, pp. 25–31, 2001. View at Publisher · View at Google Scholar · View at Scopus
  19. E. Verdaguer, E. G. Jordá, A. M. Canudas et al., “Antiapoptotic effects of roscovitine in cerebellar granule cells deprived of serum and potassium: a cell cycle-related mechanism,” Neurochemistry International, vol. 44, no. 4, pp. 251–261, 2004. View at Publisher · View at Google Scholar
  20. E. G. Jorda, E. Verdaguer, A. M. Canudas et al., “Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis,” Neuropharmacology, vol. 45, no. 5, pp. 672–683, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. I. Kruman and E. Schwartz, “Methods of neuroprotection by cyclin-dependent kinase inhibition,” US 20080182853, 2006.
  22. M. R. Barvian, E. M. Dobrusin, J. S. Kaltenbronn, et al., “Quinazolines and their use for inhibiting cyclin-dependent kinase enzymes,” US 6982260, 2006.
  23. H. Osuga, S. Osuga, F. Wang et al., “Cyclin-dependent kinases as a therapeutic target for stroke,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 18, pp. 10254–10259, 2000. View at Scopus
  24. F. Wang, D. Corbett, H. Osuga et al., “Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 2, pp. 171–182, 2002. View at Scopus
  25. S. Di Giovanni, V. Movsesyan, F. Ahmed et al., “Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 23, pp. 8333–8338, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. G. D. Hilton, B. A. Stoica, K. R. Byrnes, and A. I. Faden, “Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 11, pp. 1845–1859, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. S. Di Giovanni, S. M. Knoblach, C. Brandoli, S. A. Aden, E. P. Hoffman, and A. I. Faden, “Gene profiling in spinal cord injury shows role of cell cycle neuronal death,” Annals of Neurology, vol. 53, no. 4, pp. 454–468, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. D. S. Tian, Z. Y. Yu, M. J. Xie, B. T. Bu, O. W. Witte, and W. Wang, “Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine,” Journal of Neuroscience Research, vol. 84, no. 5, pp. 1053–1063, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. D. S. Park, A. Obeidat, A. Giovanni, and L. A. Greene, “Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment,” Neurobiology of Aging, vol. 21, no. 6, pp. 771–781, 2000. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Verdaguer, A. Jiménez, A. M. Canudas et al., “Inhibition of cell cycle pathway by flavopiridol promotes survival of cerebellar granule cells after an excitotoxic treatment,” Journal of Pharmacology and Experimental Therapeutics, vol. 308, no. 2, pp. 609–616, 2004. View at Publisher · View at Google Scholar · View at PubMed
  31. E. Verdaguer, E. G. Jordà, A. M. Canudas et al., “3-Amino thioacridone, a selective cyclin-dependent kinase 4 inhibitor, attenuates kainic acid-induced apoptosis in neurons,” Neuroscience, vol. 120, no. 3, pp. 599–603, 2003. View at Publisher · View at Google Scholar
  32. E. Verdaguer, E. G. Jordà, A. Stranges et al., “Inhibition of CDKs: a strategy for preventing kainic acid-induced apoptosis in neurons,” Annals of the New York Academy of Sciences, vol. 1010, pp. 671–674, 2003. View at Publisher · View at Google Scholar
  33. K. Lefèvre, P. G. H. Clarke, E. E. Danthe, and V. Castagné, “Involvement of cyclin-dependent kinases in axotomy-induced retinal ganglion cell death,” Journal of Comparative Neurology, vol. 447, no. 1, pp. 72–81, 2002. View at Publisher · View at Google Scholar · View at PubMed
  34. C. M. Roe, M. I. Behrens, C. Xiong, J. P. Miller, and J. C. Morris, “Alzheimer disease and cancer,” Neurology, vol. 64, no. 5, pp. 895–898, 2005. View at Scopus
  35. D. A. Bennett, “Is there a link between cancer and Alzheimer disease?” Neurology, vol. 75, no. 13, pp. 1216–1217, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. C. Becker, G. P. Brobert, S. Johansson, S. S. Jick, and C. R. Meier, “Cancer risk in association with Parkinson disease: a population-based study,” Parkinsonism and Related Disorders, vol. 16, no. 3, pp. 186–190, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. S. A. Sørensen, K. Fenger, and J. H. Olsen, “Significantly lower incidence of cancer among patients with Huntington disease: an apoptotic effect of an expanded polyglutamine tract?” Cancer, vol. 86, no. 7, pp. 1342–1346, 1999. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Hofer, M. Linnebank, and M. Weller, “Cancer risk among patients with multiple sclerosis and their parents,” Neurology, vol. 74, no. 7, pp. 614–615, 2010. View at Publisher · View at Google Scholar · View at PubMed
  39. C. M. Clements, R. S. McNally, B. J. Conti, T. W. Mak, and J. P. Y. Ting, “DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 41, pp. 15091–15096, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. R. Zanetti, S. Rosso, and D. I. Loria, “Parkinson's disease and cancer,” Cancer Epidemiology Biomarkers and Prevention, vol. 16, no. 6, p. 1081, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. A. Bajaj, J. A. Driver, and E. S. Schernhammer, “Parkinson's disease and cancer risk: a systematic review and meta-analysis,” Cancer Causes and Control, vol. 21, no. 5, pp. 697–707, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. J. J. Ferreira, D. Neutel, T. Mestre et al., “Skin cancer and Parkinson's disease,” Movement Disorders, vol. 25, no. 2, pp. 139–148, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. K. Garber, “Parkinson's disease and cancer: the unexplored connection,” Journal of the National Cancer Institute, vol. 102, no. 6, pp. 371–374, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. H. Ren, K. Fu, C. Mu, B. Li, D. Wang, and G. Wang, “DJ-1, a cancer and Parkinson's disease associated protein, regulates autophagy through JNK pathway in cancer cells,” Cancer Letters, vol. 297, no. 1, pp. 101–108, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. B. Crespi, “Autism and cancer risk,” Autism Research, vol. 4, pp. 302–310, 2011.
  46. R. Sund, E. Pukkala, and K. Patja, “Cancer incidence among persons with fragile X syndrome in Finland: a population-based study,” Journal of Intellectual Disability Research, vol. 53, no. 1, pp. 85–90, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. J. Bartkova, M. Zemanova, and J. Bartek, “Expression of CDK7/CAK in normal and tumour cells of diverse histogenesis, cell-cycle position and differentiation,” International Journal of Cancer, vol. 66, no. 6, pp. 732–737, 1996. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Ishikaw, Y. Ogihara, and M. Miura, “Visualization of radiation-induced cell cycle-associated events in tumor cells expressing the fusion protein of Azami Green and the destruction box of human Geminin,” Biochemical and Biophysical Research Communications, vol. 389, no. 3, pp. 426–430, 2009. View at Publisher · View at Google Scholar · View at PubMed
  49. P. J. Smith, N. Marquez, M. Wiltshire et al., “Mitotic bypass via an occult cell cycle phase following DNA topoisomerase II inhibition in p53 functional human tumor cells,” Cell Cycle, vol. 6, no. 16, pp. 2071–2081, 2007. View at Scopus
  50. Z. Nagy, M. M. Esiri, A. M. Cato, and A. D. Smith, “Cell cycle markers in the hippocampus in Alzheimer's disease,” Acta Neuropathologica, vol. 94, no. 1, pp. 6–15, 1997. View at Publisher · View at Google Scholar · View at Scopus
  51. A. McShea, P. L. R. Harris, K. R. Webster, A. F. Wahl, and M. A. Smith, “Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease,” American Journal of Pathology, vol. 150, no. 6, pp. 1933–1939, 1997. View at Scopus
  52. J. Busser, D. S. Geldmacher, and K. Herrup, “Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain,” Journal of Neuroscience, vol. 18, no. 8, pp. 2801–2807, 1998. View at Scopus
  53. Y. Yang, D. S. Geldmacher, and K. Herrup, “DNA replication precedes neuronal cell death in Alzheimer's disease,” Journal of Neuroscience, vol. 21, no. 8, pp. 2661–2668, 2001. View at Scopus
  54. Y. Yang, E. J. Mufson, and K. Herrup, “Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease,” Journal of Neuroscience, vol. 23, no. 7, pp. 2557–2563, 2003. View at Scopus
  55. K. L. Jordan-Sciutto, R. Dorsey, E. M. Chalovich, R. R. Hammond, and C. L. Achim, “Expression patterns of retinoblastoma protein in Parkinson disease,” Journal of Neuropathology and Experimental Neurology, vol. 62, no. 1, pp. 68–74, 2003. View at Scopus
  56. Z. Nagy and M. M. Esiri, “Neuronal cyclin expression in the hippocampus in temporal lobe epilepsy,” Experimental Neurology, vol. 150, no. 2, pp. 240–247, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. S. Ranganathan and R. Bowser, “Alterations in G1 to S phase cell-cycle regulators during amyotrophic lateral sclerosis,” American Journal of Pathology, vol. 162, no. 3, pp. 823–835, 2003. View at Scopus
  58. K. Herrup, R. Neve, S. L. Ackerman, and A. Copani, “Divide and die: cell cycle events as triggers of nerve cell death,” Journal of Neuroscience, vol. 24, no. 42, pp. 9232–9239, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. Y. Yang, N. H. Varvel, B. T. Lamb, and K. Herrup, “Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models,” Journal of Neuroscience, vol. 26, no. 3, pp. 775–784, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. V. Khurana, Y. Lu, M. L. Steinhilb, S. Oldham, J. M. Shulman, and M. B. Feany, “TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model,” Current Biology, vol. 16, no. 3, pp. 230–241, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. M. D. Nguyen, M. Boudreau, J. Kriz, S. Couillard-Després, D. R. Kaplan, and J. P. Julien, “Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1,” Journal of Neuroscience, vol. 23, no. 6, pp. 2131–2140, 2003. View at Scopus
  62. H. Imai, J. Harland, J. McCulloch, D. I. Graham, S. M. Brown, and I. M. Macrae, “Specific expression of the cell cycle regulation proteins, GADD34 and PCNA, in the peri-infarct zone after focal cerebral ischaemia in the rat,” European Journal of Neuroscience, vol. 15, no. 12, pp. 1929–1936, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. M. O'Hare, F. Wang, and D. S. Park, “Cyclin-dependent kinases as potential targets to improve stroke outcome,” Pharmacology and Therapeutics, vol. 93, no. 2-3, pp. 135–143, 2002. View at Publisher · View at Google Scholar · View at Scopus
  64. C. Y. Kuan, A. J. Schloemer, A. Lu et al., “Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain,” Journal of Neuroscience, vol. 24, no. 47, pp. 10763–10772, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. S. Veeriah, B. S. Taylor, S. Meng et al., “Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies,” Nature Genetics, vol. 42, no. 1, pp. 77–82, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. D. S. Park, S. E. Farinell, and L. A. Greene, “Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons,” Journal of Biological Chemistry, vol. 271, no. 14, pp. 8161–8169, 1996. View at Publisher · View at Google Scholar · View at Scopus
  67. D. S. Park, E. J. Morris, L. A. Greene, and H. M. Geller, “G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis,” Journal of Neuroscience, vol. 17, no. 4, pp. 1256–1270, 1997. View at Scopus
  68. A. Copani, F. Condorelli, A. Caruso et al., “Mitotic signaling by β-amyloid causes neuronal death,” FASEB Journal, vol. 13, pp. 2225–2234, 1999.
  69. N. H. Varvel, K. Bhaskar, A. R. Patil, S. W. Pimplikar, K. Herrup, and B. T. Lamb, “Aβ oligomers induce neuronal cell cycle events in Alzheimer's disease,” Journal of Neuroscience, vol. 28, no. 43, pp. 10786–10793, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. R. Williamson, T. Scales, B. R. Clark et al., “Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-β peptide exposure: involvement of Src family protein kinases,” Journal of Neuroscience, vol. 22, no. 1, pp. 10–20, 2002. View at Scopus
  71. H. Wang and G. Reiser, “Thrombin signaling in the brain: the role of protease-activated receptors,” Biological Chemistry, vol. 384, no. 2, pp. 193–202, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. M. Ohnishi, H. Katsuki, S. Fujimoto, M. Takagi, T. Kume, and A. Akaike, “Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury,” Experimental Neurology, vol. 206, no. 1, pp. 43–52, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. J. Guan, Y. Luo, and B. M. Denker, “Purkinje cell protein-2 (Pcp2) stimulates differentiation in PC12 cells by Gβγ-mediated activation of Ras and p38 MAPK,” Biochemical Journal, vol. 392, no. 2, pp. 389–397, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. J. Segarra, L. Balenci, T. Drenth, F. Maina, and F. Lamballe, “Combined signaling through ERK, PI3K/AKT, and RAC1/p38 is required for Met-triggered cortical neuron migration,” Journal of Biological Chemistry, vol. 281, no. 8, pp. 4771–4778, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. P. Lopez-Bergami and Z. Ronai, “Requirements for PKC-augmented JNK activation by MKK4/7,” International Journal of Biochemistry and Cell Biology, vol. 40, no. 5, pp. 1055–1064, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. Y. Dwivedi and G. N. Pandey, “Effects of treatment with haloperidol, chlorpromazine, and clozapine on protein kinase C (PKC) and phosphoinositide-specific phospholipase C (PI-PLC) activity and on mRNA and protein expression of PKC and PLC isozymes in rat brain,” Journal of Pharmacology and Experimental Therapeutics, vol. 291, no. 2, pp. 688–704, 1999. View at Scopus
  77. X. Zhu, C. A. Rottkamp, H. Boux, A. Takeda, G. Perry, and M. A. Smith, “Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease,” Journal of Neuropathology and Experimental Neurology, vol. 59, no. 10, pp. 880–888, 2000. View at Scopus
  78. B. Xing, T. Xin, R. L. Hunter, and G. Bing, “Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/ Akt,” Journal of Neuroinflammation, vol. 5, article 4, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. J. Tan, et al., “Neurodegenerative disease treatment using jAK/STAT inhibition,” PCT/US2008/055646, 2008.
  80. R. J. Goody, J. D. Beckham, K. Rubtsova, and K. L. Tyler, “JAK-STAT signaling pathways are activated in the brain following reovirus infection,” Journal of NeuroVirology, vol. 13, no. 4, pp. 373–383, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  81. N. Li, C. Wang, Y. Wu, X. Liu, and X. Cao, “Ca2+/calmodulin-dependent protein kinase II promotes cell cycle progression by directly activating MEK1 and subsequently modulating p27 phosphorylation,” Journal of Biological Chemistry, vol. 284, no. 5, pp. 3021–3027, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. L. M. Mao, Q. S. Tang, and J. Q. Wang, “Regulation of extracellular signal-regulated kinase phosphorylation in cultured rat striatal neurons,” Brain Research Bulletin, vol. 78, no. 6, pp. 328–334, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. S. De Bernardo, S. Canals, M. J. Casarejos, R. M. Solano, J. Menendez, and M. A. Mena, “Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures,” Journal of Neurochemistry, vol. 91, no. 3, pp. 667–682, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  84. A. Copani and F. Nicoletti, Cell-Cycle Mechanisms and Neuronal Cell Death, Kluwer Academic Publishers/Plenum, New York, NY, USA, 2005.
  85. J. Y. Qian, A. Leung, P. Harding, and M. C. LaPointe, “PGE2 stimulates human brain natriuretic peptide expression via EP4 and p42/44 MAPK,” American Journal of Physiology, vol. 290, no. 5, pp. H1740–H1746, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. B. L. Fiebich, S. Schleicher, O. Spleiss, M. Czygan, and M. Hüll, “Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes: possible involvement of EP4-like receptors, p38 mitogen-activated protein kinase and protein kinase C,” Journal of Neurochemistry, vol. 79, no. 5, pp. 950–958, 2001. View at Publisher · View at Google Scholar · View at Scopus
  87. D. Darmoul, V. Gratio, H. Devaud, T. Lehy, and M. Laburthe, “Aberrant expression and activation of the thrombin receptor protease-activated receptor-1 induces cell proliferation and motility in human colon cancer cells,” American Journal of Pathology, vol. 162, no. 5, pp. 1503–1513, 2003. View at Scopus
  88. L. Traby, A. Kaider, R. Schmid et al., “The effects of low-molecular-weight heparin at two different dosages on thrombin generation in cancer patients: a randomised controlled trial,” Thrombosis and Haemostasis, vol. 104, no. 1, pp. 92–99, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. K. M. Snyder and C. M. Kessler, “The pivotal role of thrombin in cancer biology and tumorigenesis,” Seminars in Thrombosis and Hemostasis, vol. 34, no. 8, pp. 734–741, 2008. View at Publisher · View at Google Scholar · View at PubMed
  90. H. Wang and G. Reiser, “The role of the Ca2+-sensitive tyrosine kinase Pyk2 and Src in thrombin signalling in rat astrocytes,” Journal of Neurochemistry, vol. 84, no. 6, pp. 1349–1357, 2003. View at Publisher · View at Google Scholar · View at Scopus
  91. D. Z. Liu, X. Y. Cheng, B. P. Ander et al., “Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons,” Neurobiology of Disease, vol. 30, no. 2, pp. 201–211, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. S. Fujimoto, H. Katsuki, M. Ohnishi, M. Takagi, T. Kume, and A. Akaike, “Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo,” Neuroscience, vol. 144, no. 2, pp. 694–701, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  93. G. Driessens, L. Harsan, P. Browaeys, X. Giannakopoulos, T. Velu, and C. Bruyns, “Assessment of in vivo chemotherapy-induced DNa damage in a p53-mutated rat tumor by micronuclei assay,” Annals of the New York Academy of Sciences, vol. 1010, pp. 775–779, 2003. View at Publisher · View at Google Scholar · View at Scopus
  94. G. Van Kaick and S. Delorme, “Therapy-induced effects in normal tissue,” Radiologe, vol. 48, no. 9, pp. 871–880, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. K. Lucas, M. J. Gula, and J. Blatt, “Relapse in acute lymphoblastic leukemia as a function of white blood cell and absolute neutrophil counts during maintenance chemotherapy,” Pediatric Hematology and Oncology, vol. 9, no. 2, pp. 91–97, 1992. View at Scopus
  96. J. S. Wefel, A. K. Saleeba, A. U. Buzdar, and C. A. Meyers, “Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer,” Cancer, vol. 116, no. 14, pp. 3348–3356, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. C. B. Harrington, J. A. Hansen, M. Moskowitz, B. L. Todd, and M. Feuerstein, “It's not over when it's over: long-term symptoms in cancer survivors—a systematic review,” International Journal of Psychiatry in Medicine, vol. 40, no. 2, pp. 163–181, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. J. Dietrich, M. Monje, J. Wefel, and C. Meyers, “Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy,” Oncologist, vol. 13, no. 12, pp. 1285–1295, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. M. J. B. Taphoorn and M. Klein, “Cognitive deficits in adult patients with brain tumours,” Lancet Neurology, vol. 3, no. 3, pp. 159–168, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  100. T. N. Byrne, “Cognitive sequelae of brain tumor treatment,” Current Opinion in Neurology, vol. 18, no. 6, pp. 662–666, 2005. View at Scopus
  101. M.-E. Brière, J. G. Scott, R. Y. McNall-Knapp, and R. L. Adams, “Cognitive outcome in pediatric brain tumor survivors: delayed attention deficit at long-term follow-up,” Pediatric Blood and Cancer, vol. 50, no. 2, pp. 337–340, 2008. View at Publisher · View at Google Scholar · View at PubMed
  102. K. Hilverda, I. Bosma, J. J. Heimans et al., “Cognitive functioning in glioblastoma patients during radiotherapy and temozolomide treatment: initial findings,” Journal of Neuro-Oncology, vol. 97, no. 1, pp. 89–94, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  103. A. Talacchi, B. Santini, S. Savazzi, and M. Gerosa, “Cognitive effects of tumour and surgical treatment in glioma patients,” Journal of Neuro-Oncology, vol. 103, no. 3, pp. 541–549, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  104. D. D. Correa, “Cognitive functions in brain tumor patients,” Hematology/Oncology Clinics of North America, vol. 20, no. 6, pp. 1363–1376, 2006. View at Publisher · View at Google Scholar · View at PubMed
  105. J. C. Marsh, B. T. Gielda, A. M. Herskovic, and R. A. Abrams, “Cognitive sparing during the administration of whole brain radiotherapy and prophylactic cranial irradiation: current concepts and approaches,” Journal of Oncology, vol. 2010, Article ID 198208, 16 pages, 2010. View at Publisher · View at Google Scholar · View at PubMed
  106. M. D. Brandt and A. Storch, “Neurogenesis in the adult brain: from bench to bedside?” Fortschritte der Neurologie Psychiatrie, vol. 76, no. 9, pp. 517–529, 2008. View at Publisher · View at Google Scholar · View at PubMed
  107. J. Shen, L. Xie, X. Mao et al., “Neurogenesis after primary intracerebral hemorrhage in adult human brain,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 8, pp. 1460–1468, 2008. View at Publisher · View at Google Scholar · View at PubMed
  108. B. Neundörfer, “Does the neurogenesis in the adult brain show the way into the future?” Fortschritte der Neurologie Psychiatrie, vol. 76, no. 9, p. 511, 2008. View at Publisher · View at Google Scholar · View at PubMed
  109. J. Liu, K. Solway, R. O. Messing, and F. R. Sharp, “Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils,” Journal of Neuroscience, vol. 18, no. 19, pp. 7768–7778, 1998. View at Scopus
  110. A. Abdipranoto, S. Wu, S. Stayte, and B. Vissel, “The role of neurogenesis in neurodegenerative diseases and its implications for therapeutic development,” CNS and Neurological Disorders, vol. 7, no. 2, pp. 187–210, 2008. View at Publisher · View at Google Scholar · View at Scopus
  111. V. Chesnokova and R. N. Pechnick, “Antidepressants and Cdk inhibitors: releasing the brake on neurogenesis?” Cell Cycle, vol. 7, no. 15, pp. 2321–2326, 2008. View at Scopus
  112. J. J. Ohab, S. Fleming, A. Blesch, and S. T. Carmichael, “A neurovascular niche for neurogenesis after stroke,” Journal of Neuroscience, vol. 26, no. 50, pp. 13007–13016, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  113. T. D. Palmer, A. R. Willhoite, and F. H. Gage, “Vascular niche for adult hippocampal neurogenesis,” Journal of Comparative Neurology, vol. 425, no. 4, pp. 479–494, 2000. View at Publisher · View at Google Scholar · View at Scopus
  114. P. S. Eriksson, E. Perfilieva, T. Björk-Eriksson et al., “Neurogenesis in the adult human hippocampus,” Nature Medicine, vol. 4, no. 11, pp. 1313–1317, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  115. N. S. Roy, S. Wang, L. Jiang et al., “In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus,” Nature Medicine, vol. 6, no. 3, pp. 271–277, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. F. Doetsch, I. Caille, D. A. Lim, J. M. Garcia-Verdugo, and A. Alvarez-Buylla, “Subventricular zone astrocytes are neural stem cells in the adult mammalian brain,” Cell, vol. 97, no. 6, pp. 703–716, 1999. View at Publisher · View at Google Scholar · View at Scopus
  117. C. M. Morshead, B. A. Reynolds, C. G. Craig et al., “Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells,” Neuron, vol. 13, no. 5, pp. 1071–1082, 1994. View at Publisher · View at Google Scholar · View at Scopus
  118. D.-Z. Liu, B. P. Ander, H. Xu et al., “Blood-brain barrier breakdown and repair by Src after thrombin-induced injury,” Annals of Neurology, vol. 67, no. 4, pp. 526–533, 2010. View at Publisher · View at Google Scholar · View at PubMed
  119. S. Becker, “A computational principle for hippocampal learning and neurogenesis,” Hippocampus, vol. 15, no. 6, pp. 722–738, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  120. J. B. Aimone, J. Wiles, and F. H. Gage, “Potential role for adult neurogenesis in the encoding of time in new memories,” Nature Neuroscience, vol. 9, no. 6, pp. 723–727, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  121. J. Fallon, S. Reid, R. Kinyamu et al., “In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 26, pp. 14686–14691, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  122. L. S. Schneider, K. S. Dagerman, J. P. T. Higgins, and R. McShane, “Lack of evidence for the efficacy of memantine in mild Alzheimer disease,” Archives of Neurology, vol. 68, no. 8, pp. 991–998, 2011. View at Publisher · View at Google Scholar · View at PubMed
  123. M. Suzuki, A. D. Nelson, J. B. Eickstaedt, K. Wallace, L. S. Wright, and C. N. Svendsen, “Glutamate enhances proliferation and neurogenesis in human neural progenitor cell cultures derived from the fetal cortex,” European Journal of Neuroscience, vol. 24, no. 3, pp. 645–653, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  124. X. Zhang, E. D. Yeung, J. Wang et al., “Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cells,” Clinical and Experimental Pharmacology and Physiology, vol. 37, no. 8, pp. 841–847, 2010. View at Publisher · View at Google Scholar · View at PubMed
  125. K. Abe, “Neuroprotective therapy for ischemic stroke with free radical scavenger and gene-stem cell therapy,” Clinical Neurology, vol. 48, no. 11, pp. 896–898, 2008.
  126. C. X. Wang and A. Shuaib, “Neuroprotective effects of free radical scavengers in stroke,” Drugs and Aging, vol. 24, no. 7, pp. 537–546, 2007. View at Publisher · View at Google Scholar · View at Scopus
  127. K. Eerman and H. Brodaty, “Tocopherol (vitamin E) in Alzheimer's disease and other neurodegenerative disorders,” CNS Drugs, vol. 18, no. 12, pp. 807–825, 2004. View at Publisher · View at Google Scholar · View at Scopus
  128. J. Viña, A. Lloret, R. Ortí, and D. Alonso, “Molecular bases of the treatment of Alzheimer's disease with antioxidants: prevention of oxidative stress,” Molecular Aspects of Medicine, vol. 25, no. 1-2, pp. 117–123, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  129. K. W. Park and B. K. Jin, “Thrombin-induced oxidative stress contributes to the death of hippocampal neurons: role of neuronal NADPH oxidase,” Journal of Neuroscience Research, vol. 86, no. 5, pp. 1053–1063, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  130. G. Levy, P. Kaufmann, R. Buchsbaum et al., “A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS,” Neurology, vol. 66, no. 5, pp. 660–663, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  131. K. L. Ferrante, J. Shefner, H. Zhang et al., “Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS,” Neurology, vol. 65, no. 11, pp. 1834–1836, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  132. H. Yoshino and A. Kimura, “Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).,” Amyotrophic Lateral Sclerosis, vol. 7, no. 4, pp. 241–245, 2006. View at Scopus
  133. H. Ito, R. Wate, J. Zhang et al., “Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice,” Experimental Neurology, vol. 213, no. 2, pp. 448–455, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  134. W. J. Yuan, T. Yasuhara, T. Shingo et al., “Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons,” BMC Neuroscience, vol. 9, article 75, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  135. M. Tanabe, Y. Nagatani, K. Saitoh, K. Takasu, and H. Ono, “Pharmacological assessments of nitric oxide synthase isoforms and downstream diversity of NO signaling in the maintenance of thermal and mechanical hypersensitivity after peripheral nerve injury in mice,” Neuropharmacology, vol. 56, no. 3, pp. 702–708, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  136. L. Vanella, C. Di Giacomo, R. Acquaviva et al., “The DDAH/NOS pathway in human prostatic cancer cell lines: antiangiogenic effect of L-NAME,” International Journal of Oncology, vol. 39, no. 5, pp. 1303–1310, 2011. View at Publisher · View at Google Scholar · View at PubMed
  137. D. Y. Lee, K. W. Park, and B. K. Jin, “Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro: proteolytic and non-proteolytic actions,” Biochemical and Biophysical Research Communications, vol. 346, no. 3, pp. 727–738, 2006. View at Publisher · View at Google Scholar · View at PubMed
  138. A. L. Sabichi, J. J. Lee, H. B. Grossman, et al., “A randomized controlled trial of celecoxib to prevent recurrence of non-muscle-invasive bladder cancer,” Cancer Prevention Research, vol. 4, no. 10, pp. 1580–1589, 2011.
  139. A. Koch, B. Bergman, E. Holmberg et al., “Effect of celecoxib on survival in patients with advanced non-small cell lung cancer: a double blind randomised clinical phase III trial (CYCLUS study) by the Swedish Lung Cancer Study Group,” European Journal of Cancer, vol. 47, no. 10, pp. 1546–1555, 2011. View at Publisher · View at Google Scholar · View at PubMed
  140. C. Gridelli, C. Gallo, A. Ceribelli et al., “Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study,” Lancet Oncology, vol. 8, no. 6, pp. 500–512, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  141. J. Kao, E. M. Genden, C.-T. Chen et al., “Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer,” Cancer, vol. 117, no. 14, pp. 3173–3181, 2011. View at Publisher · View at Google Scholar · View at PubMed
  142. A. Lipton, C. Campbell-Baird, L. Witters, H. Harvey, and S. Ali, “Phase II trial of gemcitabine, irinotecan, and celecoxib in patients with advanced pancreatic cancer,” Journal of Clinical Gastroenterology, vol. 44, no. 4, pp. 286–288, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  143. E. S. Antonarakis, E. I. Heath, J. R. Walczak et al., “Phase II, randomized, placebo-controlled trial of neoadjuvant celecoxib in men with clinically localized prostate cancer: evaluation of drug-specific biomarkers,” Journal of Clinical Oncology, vol. 27, no. 30, pp. 4986–4993, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  144. A. Fabi, G. Metro, P. Papaldo et al., “Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation,” Cancer Chemotherapy and Pharmacology, vol. 62, no. 4, pp. 717–725, 2008. View at Publisher · View at Google Scholar · View at PubMed
  145. R. S. Midgley, C. C. McConkey, E. C. Johnstone et al., “Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial,” Journal of Clinical Oncology, vol. 28, no. 30, pp. 4575–4580, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  146. M. Youns, T. Efferth, and J. D. Hoheisel, “Transcript profiling identifies novel key players mediating the growth inhibitory effect of NS-398 on human pancreatic cancer cells,” European Journal of Pharmacology, vol. 650, no. 1, pp. 170–177, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  147. A. B. Fernández-Martínez, A. M. Bajo, A. Valdehita et al., “Multifunctional role of VIP in prostate cancer progression in a xenograft model: suppression by curcumin and COX-2 inhibitor NS-398,” Peptides, vol. 30, no. 12, pp. 2357–2364, 2009. View at Publisher · View at Google Scholar · View at PubMed
  148. L. Zhang, J. Tu, Z.-L. Yu, Y.-D. Wu, C.-M. Xu, and S.-T. Zhang, “Effects of the inhibition of cyclooxygenase-2 on human esophageal cancer cells: inhibition of cell proliferation and induction of apoptosis,” Pathology and Oncology Research, vol. 16, no. 1, pp. 39–45, 2010. View at Publisher · View at Google Scholar · View at PubMed
  149. N. Banu, A. Buda, S. Chell et al., “Inhibition of COX-2 with NS-398 decreases colon cancer cell motility through blocking epidermal growth factor receptor transactivation: possibilities for combination therapy,” Cell Proliferation, vol. 40, no. 5, pp. 768–779, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  150. T. D. Warner and J. A. Mitchell, “Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic,” FASEB Journal, vol. 18, no. 7, pp. 790–804, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  151. M. Etminan, S. Gill, and A. Samii, “Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies,” British Medical Journal, vol. 327, no. 7407, pp. 128–131, 2003. View at Scopus
  152. J. H. Heo, H. N. Seo, Y. J. Choe et al., “T-type Ca2+ channel blockers suppress the growth of human cancer cells,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 14, pp. 3899–3901, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  153. C. L. Franke, R. Palm, M. Dalby et al., “Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands,” Acta Neurologica Scandinavica, vol. 93, no. 1, pp. 56–60, 1996.
  154. W. G. North, G. Gao, V. A. Memoli, R. H. Pang, and L. Lynch, “Breast cancer expresses functional NMDA receptors,” Breast Cancer Research and Treatment, vol. 122, no. 2, pp. 307–314, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  155. H. Yang, M. Chopp, F. Jiang, X. Zhang, and T. Schallert, “Interruption of functional recovery by the NMDA glutamate antagonist MK801 after compression of the sensorimotor cortex: implications for treatment of tumors or other mass-related brain injuries,” Experimental Neurology, vol. 200, no. 1, pp. 262–266, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  156. J. Andrews, “Amyotrophic lateral sclerosis: clinical management and research update,” Current Neurology and Neuroscience Reports, vol. 9, no. 1, pp. 59–68, 2009. View at Publisher · View at Google Scholar · View at Scopus
  157. T. K. McIntosh, D. H. Smith, M. Voddi, B. R. Perri, and J.-M. Stutzmann, “Riluzole, a novel neuroprotective agent, attenuates both neurologic motor and cognitive dysfunction following experimental brain injury in the rat,” Journal of Neurotrauma, vol. 13, no. 12, pp. 767–780, 1996.
  158. L. Belayev, O. F. Alonso, Y. Liu et al., “Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats,” Journal of Neurotrauma, vol. 18, no. 10, pp. 1031–1038, 2001.
  159. P. H. Kitzman, “Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat,” Neuroscience Letters, vol. 455, no. 2, pp. 150–153, 2009. View at Publisher · View at Google Scholar · View at PubMed
  160. T. D. Ardizzone, A. Lu, K. R. Wagner, Y. Tang, R. Ran, and F. R. Sharp, “Glutamate receptor blockade attenuates glucose hypermetabolism in perihematomal brain after experimental intracerebral hemorrhage in rat,” Stroke, vol. 35, no. 11, pp. 2587–2591, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  161. P. Meden, K. Overgaard, T. Sereghy, and G. Boysen, “Enhancing the efficacy of thrombolysis by AMPA receptor blockade with NBQX in a rat embolic stroke model,” Journal of the Neurological Sciences, vol. 119, no. 2, pp. 209–216, 1993. View at Publisher · View at Google Scholar · View at Scopus
  162. K. Watanabe, T. Kanno, T. Oshima, H. Miwa, C. Tashiro, and T. Nishizaki, “The NMDA receptor NR2A subunit regulates proliferation of MKN45 human gastric cancer cells,” Biochemical and Biophysical Research Communications, vol. 367, no. 2, pp. 487–490, 2008. View at Publisher · View at Google Scholar · View at PubMed
  163. W. Danysz and C. G. Parsons, “The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence,” International Journal of Geriatric Psychiatry, vol. 18, no. 1, pp. S23–S32, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  164. J. L. Molinuevo, A. Lladó, and L. Rami, “Memantine: targeting glutamate excitotoxicity in Alzheimer's disease and other dementias,” American Journal of Alzheimer's Disease and other Dementias, vol. 20, no. 2, pp. 77–85, 2005.
  165. D. M. Robinson and G. M. Keating, “Memantine: a review of its use in Alzheimer's disease,” Drugs, vol. 66, no. 11, pp. 1515–1534, 2006. View at Publisher · View at Google Scholar · View at Scopus
  166. A. Iraqi and T. L. Hughes, “Nightmares and memantine: a case report and review of literature,” Journal of the American Medical Directors Association, vol. 10, no. 1, pp. 77–78, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  167. K. Zdanys and R. R. Tampi, “A systematic review of off-label uses of memantine for psychiatric disorders,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 32, no. 6, pp. 1362–1374, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  168. V. L. Raghavendra Rao, A. Dogan, K. G. Todd, K. K. Bowen, and R. J. Dempsey, “Neuroprotection by memantine, a non-competitive NMDA receptor antagonist after traumatic brain injury in rats,” Brain Research, vol. 911, no. 1, pp. 96–100, 2001. View at Publisher · View at Google Scholar
  169. S.-T. Lee, K. Chu, K.-H. Jung et al., “Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement,” Journal of Cerebral Blood Flow and Metabolism, vol. 26, no. 4, pp. 536–544, 2006. View at Publisher · View at Google Scholar · View at PubMed
  170. C. S. Babu and M. Ramanathan, “Pre-ischemic treatment with memantine reversed the neurochemical and behavioural parameters but not energy metabolites in middle cerebral artery occluded rats,” Pharmacology Biochemistry and Behavior, vol. 92, no. 3, pp. 424–432, 2009. View at Publisher · View at Google Scholar · View at PubMed
  171. L. Yu, H. G. Garg, B. Li, R. J. Linhardt, and C. A. Hales, “Antitumor effect of butanoylated heparin with low anticoagulant activity on lung cancer growth in mice and rats,” Current Cancer Drug Targets, vol. 10, no. 2, pp. 229–241, 2010. View at Publisher · View at Google Scholar · View at Scopus
  172. R. Mikulík, M. Dufek, D. Goldemund, and M. Reif, “A pilot study on systemic thrombolysis followed by low molecular weight heparin in ischemic stroke,” European Journal of Neurology, vol. 13, no. 10, pp. 1106–1111, 2006. View at Publisher · View at Google Scholar · View at PubMed
  173. Z. Sun, Z. Zhao, S. Zhao et al., “Recombinant hirudin treatment modulates aquaporin-4 and aquaporin-9 expression after intracerebral hemorrhage in vivo,” Molecular Biology Reports, vol. 36, no. 5, pp. 1119–1127, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  174. M. Xue, M. D. Hollenberg, and V. W. Yong, “Combination of thrombin and matrix metalloproteinase-9 exacerbates neurotoxicity in cell culture and intracerebral hemorrhage in mice,” Journal of Neuroscience, vol. 26, no. 40, pp. 10281–10291, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  175. T. Goerge, A. Barg, E. M. Schnaeker et al., “Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation,” Cancer Research, vol. 66, no. 15, pp. 7766–7774, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  176. C. E. Junge, T. Sugawara, G. Mannaioni et al., “The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 22, pp. 13019–13024, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  177. C. E. Hamill, W. M. Caudle, J. R. Richardson et al., “Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson's disease by the G-protein-coupled receptor protease-activated receptor 1,” Molecular Pharmacology, vol. 72, no. 3, pp. 653–664, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  178. M. T. Acosta, P. G. Kardel, K. S. Walsh, K. N. Rosenbaum, G. A. Gioia, and R. J. Packer, “Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: phase I study,” Pediatric Neurology, vol. 45, no. 4, pp. 241–245, 2011. View at Publisher · View at Google Scholar · View at PubMed
  179. J. J. Knox, L. L. Siu, E. Chen et al., “A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix,” European Journal of Cancer, vol. 41, no. 4, pp. 523–530, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  180. B. Barkan, S. Starinsky, E. Friedman, R. Stein, and Y. Kloog, “The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1,” Clinical Cancer Research, vol. 12, no. 18, pp. 5533–5542, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  181. L. Björkhem-Bergman, J. Acimovic, U. B. Torndal, P. Parini, and L. C. Eriksson, “Lovastatin prevents carcinogenesis in a rat model for liver cancer. Effects of ubiquinone supplementation,” Anticancer Research, vol. 30, no. 4, pp. 1105–1112, 2010. View at Scopus
  182. A. Martirosyan, J. W. Clendening, C. A. Goard, and L. Z. Penn, “Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance,” BMC Cancer, vol. 10, article 103, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  183. J. Klawitter, T. Shokati, V. Moll, U. Christians, and J. Klawitter, “Effects of lovastatin on breast cancer cells: a proteo-metabonomic study,” Breast Cancer Research, vol. 12, no. 2, article R16, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  184. J. Lee, I. Lee, C. Park, and W. K. Kang, “Lovastatin-induced RhoA modulation and its effect on senescence in prostate cancer cells,” Biochemical and Biophysical Research Communications, vol. 339, no. 3, pp. 748–754, 2006. View at Publisher · View at Google Scholar · View at PubMed
  185. I. H. Park, J. Y. Kim, J. I. Jung, and J. Y. Han, “Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations,” Investigational New Drugs, vol. 28, no. 6, pp. 791–799, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  186. M. S. V. Elkind, R. L. Sacco, R. B. Macarthur et al., “The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke,” International Journal of Stroke, vol. 3, no. 3, pp. 210–218, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  187. M. S. V. Elkind, R. L. Sacco, R. B. MacArthur et al., “High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART),” Cerebrovascular Diseases, vol. 28, no. 3, pp. 266–275, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  188. I. V. Smirnova, B. A. Citron, P. M. Arnold, and B. W. Festoff, “Neuroprotective signal transduction in model motor neurons exposed to thrombin: G-protein modulation effects on neurite outgrowth, Ca2+ mobilization, and apoptosis,” Journal of Neurobiology, vol. 48, no. 2, pp. 87–100, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  189. D. D. Cunningham, “Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities,” Journal of Neuroscience, vol. 17, no. 14, pp. 5316–5326, 1997.
  190. C. I. Herold, V. Chadaram, B. L. Peterson et al., “Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing,” Clinical Cancer Research, vol. 17, no. 18, pp. 6061–6070, 2011. View at Publisher · View at Google Scholar · View at PubMed
  191. A. Gucalp, J. A. Sparano, J. Caravelli, et al., “Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer,” Clinical Breast Cancer, vol. 11, no. 5, pp. 306–311, 2011.
  192. M. Anbalagan, L. Carrier, S. Glodowski, D. Hangauer, B. Shan, and B. G. Rowan, “KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor alpha positive breast cancer,” Breast Cancer Research and Treatment. In press.
  193. B. Pohorelic, R. Singh, S. Parkin, et al., “Role of Src in breast cancer cell migration and invasion in a breast cell/bone-derived cell microenvironment,” Breast Cancer Research and Treatment. In press.
  194. P. Ceppi, I. Rapa, M. Lo Iacono, et al., “Expression and pharmacological inhibition of thymidylate synthase and Src kinase in nonsmall cell lung cancer,” International Journal of Cancer. In press.
  195. G. W. Krystal, C. S. DeBerry, D. Linnekin, and J. Litz, “Lck associates with and is activated by kit in a small cell lung cancer cell line: inhibition of SCF-mediated growth by the Src family kinase inhibitor PP1,” Cancer Research, vol. 58, no. 20, pp. 4660–4666, 1998. View at Scopus
  196. L. Kong, Z. Deng, H. Shen, and Y. Zhang, “Src family kinase inhibitor PP2 efficiently inhibits cervical cancer cell proliferation through down-regulating phospho-Src-Y416 and phospho-EGFR-Y1173,” Molecular and Cellular Biochemistry, vol. 348, no. 1-2, pp. 11–19, 2011. View at Publisher · View at Google Scholar · View at PubMed
  197. E. Fujimoto, H. Sato, Y. Nagashima et al., “A Src family inhibitor (PP1) potentiates tumor-suppressive effect of connexin 32 gene in renal cancer cells,” Life Sciences, vol. 76, no. 23, pp. 2711–2720, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  198. L. Li, C. H. Ren, S. A. Tahir, C. Ren, and T. C. Thompson, “Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A,” Molecular and Cellular Biology, vol. 23, no. 24, pp. 9389–9404, 2003. View at Publisher · View at Google Scholar · View at Scopus
  199. T. D. Ardizzone, X. Zhan, B. P. Ander, and F. R. Sharp, “Src kinase inhibition improves acute outcomes after experimental intracerebral hemorrhage,” Stroke, vol. 38, no. 5, pp. 1621–1625, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  200. I. A. Siddiqui, M. Asim, B. B. Hafeez, V. M. Adhami, R. S. Tarapore, and H. Mukhtar, “Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer,” FASEB Journal, vol. 25, no. 4, pp. 1198–1207, 2011. View at Publisher · View at Google Scholar · View at PubMed
  201. T. Sen, A. Dutta, and A. Chatterjee, “Epigallocatechin-3-gallate (EGCG) downregulates gelatinase-B (MMP-9) by involvement of FAK/ERK/NFκB and AP-1 in the human breast cancer cell line MDA-MB-231,” Anti-Cancer Drugs, vol. 21, no. 6, pp. 632–644, 2010. View at Publisher · View at Google Scholar · View at Scopus
  202. S. A. Milligan, P. Burke, D. T. Coleman et al., “The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells,” Clinical Cancer Research, vol. 15, no. 15, pp. 4885–4894, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  203. S. Shankar, S. Ganapathy, S. R. Hingorani, and R. K. Srivastava, “EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer,” Frontiers in Bioscience, vol. 13, no. 2, pp. 440–452, 2008. View at Publisher · View at Google Scholar
  204. S. Faderl, A. Ferrajoli, D. Harris, Q. Van, W. Priebe, and Z. Estrov, “WP-1034, a novel JAK-STAT inhibitor, with proapoptotic and antileukemic activity in acute myeloid leukemia (AML),” Anticancer Research, vol. 25, no. 3 B, pp. 1841–1850, 2005. View at Scopus
  205. A. Shakoori, W. Mai, K. Miyashita et al., “Inhibition of GSK-3β activity attenuates proliferation of human colon cancer cells in rodents,” Cancer Science, vol. 98, no. 9, pp. 1388–1393, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  206. J. G. Pizarro, J. Folch, J. L. Esparza, J. Jordan, M. Pallàs, and A. Camins, “A molecular study of pathways involved in the inhibition of cell proliferation in neuroblastoma B65 cells by the GSK-3 inhibitors lithium and SB-415286,” Journal of Cellular and Molecular Medicine, vol. 13, no. 9 B, pp. 3906–3917, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  207. M. Pallàs and A. Camins, “Molecular and biochemical features in Alzheimer's disease,” Current Pharmaceutical Design, vol. 12, no. 33, pp. 4389–4408, 2006. View at Publisher · View at Google Scholar
  208. R. V. Bhat, S. L. Budd Haeberlein, and J. Avila, “Glycogen synthase kinase 3: a drug target for CNS therapies,” Journal of Neurochemistry, vol. 89, no. 6, pp. 1313–1317, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  209. D. A. E. Cross, A. A. Culbert, K. A. Chalmers, L. Facci, S. D. Skaper, and A. D. Reith, “Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death,” Journal of Neurochemistry, vol. 77, no. 1, pp. 94–102, 2001. View at Publisher · View at Google Scholar · View at Scopus
  210. R. S. Jope and G. V. W. Johnson, “The glamour and gloom of glycogen synthase kinase-3,” Trends in Biochemical Sciences, vol. 29, no. 2, pp. 95–102, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  211. N. Dunn, C. Holmes, and M. Mullee, “Does lithium therapy protect against the onset of dementia?” Alzheimer Disease and Associated Disorders, vol. 19, no. 1, pp. 20–22, 2005. View at Publisher · View at Google Scholar · View at Scopus
  212. Y. Su, J. Ryder, B. Li et al., “Lithium, a common drug for bipolar disorder treatment, regulates amyloid-β precursor protein processing,” Biochemistry, vol. 43, no. 22, pp. 6899–6908, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  213. E. S. Chung, E. Bok, S. Sohn, Y. D. Lee, H. H. Baik, and B. K. Jin, “GT1b-induced neurotoxicity is mediated by the Akt/GSK-3/tau signaling pathway but not caspase-3 in mesencephalic dopaminergic neurons,” BMC Neuroscience, vol. 11, article 74, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  214. H. Jiang, W. Guo, X. Liang, and Y. Rao, “Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3β and its upstream regulators,” Cell, vol. 120, no. 1, pp. 123–135, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  215. F. Fornai, P. Longone, L. Cafaro et al., “Lithium delays progression of amyotrophic lateral sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 6, pp. 2052–2057, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  216. E. Leung, J. E. Kim, G. W. Rewcastle, G. J. Finlay, and B. C. Baguley, “Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells,” Cancer Biology and Therapy, vol. 11, no. 11, pp. 938–946, 2011. View at Publisher · View at Google Scholar
  217. L. Zhao, B. Teter, T. Morihara et al., “Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention,” Journal of Neuroscience, vol. 24, no. 49, pp. 11120–11126, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  218. S.-N. Kim, S.-T. Kim, A.-R. Doo et al., “Phosphatidylinositol 3-kinase/Akt signaling pathway mediates acupuncture-induced dopaminergic neuron protection and motor function improvement in a mouse model of parkinson's disease,” International Journal of Neuroscience, vol. 121, no. 10, pp. 562–569, 2011. View at Publisher · View at Google Scholar · View at PubMed
  219. L. Van Ummersen, K. Binger, J. Volkman et al., “A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer,” Clinical Cancer Research, vol. 10, no. 22, pp. 7450–7456, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  220. S. K. Pal, K. Reckamp, H. Yu, and R. A. Figlin, “Akt inhibitors in clinical development for the treatment of cancer,” Expert Opinion on Investigational Drugs, vol. 19, no. 11, pp. 1355–1366, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  221. “(1995–2011) FDA Approved Drugs for Oncology,” http://www.centerwatch.com/drug-information/fda-approvals/drug-areas.aspx?AreaID=12.
  222. K. Behbakht, M. W. Sill, K. M. Darcy et al., “Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies. A Gynecologic Oncology Group study,” Gynecologic Oncology, vol. 123, no. 1, pp. 19–26, 2011. View at Publisher · View at Google Scholar · View at PubMed
  223. A. M. Oza, L. Elit, M.-S. Tsao et al., “Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group,” Journal of Clinical Oncology, vol. 29, no. 24, pp. 3278–3285, 2011. View at Publisher · View at Google Scholar · View at PubMed
  224. S. Chan, M. E. Scheulen, S. Johnston et al., “Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer,” Journal of Clinical Oncology, vol. 23, no. 23, pp. 5314–5322, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  225. E. Galanis, J. C. Buckner, M. J. Maurer et al., “Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study,” Journal of Clinical Oncology, vol. 23, no. 23, pp. 5294–5304, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  226. I. Duran, J. Kortmansky, D. Singh et al., “A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas,” British Journal of Cancer, vol. 95, no. 9, pp. 1148–1154, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  227. K. J. Pandya, S. Dahlberg, M. Hidalgo et al., “A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500),” Journal of Thoracic Oncology, vol. 2, no. 11, pp. 1036–1041, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  228. H. Gerullis, T. H. Ecke, B. Janusch et al., “Long-term response in advanced bladder cancer involving the use of temsirolimus and vinflunine after platin resistance,” Anti-Cancer Drugs, vol. 22, no. 9, pp. 940–943, 2011. View at Publisher · View at Google Scholar · View at PubMed
  229. D. Zardavas, A. Meisel, P. Samaras et al., “Temsirolimus is highly effective as third-line treatment in chromophobe renal cell cancer,” Case Reports in Oncology, vol. 4, no. 1, pp. 16–18, 2011. View at Publisher · View at Google Scholar · View at PubMed
  230. G. Hudes, M. Carducci, P. Tomczak et al., “Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma,” New England Journal of Medicine, vol. 356, no. 22, pp. 2271–2281, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  231. P. Spilman, N. Podlutskaya, M. J. Hart et al., “Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of alzheimer's disease,” PLoS ONE, vol. 5, no. 4, article e9979, 2010. View at Publisher · View at Google Scholar · View at PubMed
  232. C. Malagelada, Z. H. Jin, V. Jackson-Lewis, S. Przedborski, and L. A. Greene, “Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease,” Journal of Neuroscience, vol. 30, no. 3, pp. 1166–1175, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  233. S. Chen, C. M. Atkins, C. L. Liu, O. F. Alonso, W. D. Dietrich, and B. R. Hu, “Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 5, pp. 939–949, 2007. View at Publisher · View at Google Scholar · View at PubMed
  234. J. Park, J. Zhang, J. Qiu et al., “Combination therapy targeting Akt and mammalian target of rapamycin improves functional outcome after controlled cortical impact in mice,” Journal of Cerebral Blood Flow and Metabolism. In press. View at Publisher · View at Google Scholar · View at PubMed
  235. S. Codeluppi, C. I. Svensson, M. P. Hefferan et al., “The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord,” Journal of Neuroscience, vol. 29, no. 4, pp. 1093–1104, 2009. View at Publisher · View at Google Scholar · View at PubMed
  236. A. Sekiguchi, H. Kanno, H. Ozawa, S. Yamaya, and E. Itoi, “Rapamycin Promotes Autophagy and Reduces Neural Tissue Damage and Locomotor Impairment after Spinal Cord Injury in Mice,” Journal of Neurotrauma. In press.
  237. A. Chauhan, U. Sharma, N. R. Jagannathan, K. H. Reeta, and Y. K. Gupta, “Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats,” Behavioural Brain Research, vol. 225, no. 2, pp. 603–609, 2011. View at Publisher · View at Google Scholar · View at PubMed
  238. A. Jimeno, G. Hallur, A. Chan et al., “Development of two novel benzoylphenylurea sulfur analogues and evidence that the microtubule-associated protein tau is predictive of their activity in pancreatic cancer,” Molecular Cancer Therapeutics, vol. 6, no. 5, pp. 1509–1516, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  239. TauRx-Therapeutics-Ltd, “TRx0014 in Patients With Mild or Moderate Alzheimer's Disease. ClinicalTrials.gov Identifier: NCT00515333,” 2007, http://clinicaltrials.gov/ct2/show/NCT00515333?spons=%22TauRx+Therapeutics+Ltd%22&spons_ex=Y&rank=1.
  240. M. Williams, “Progress in Alzheimer's disease drug discovery: an update,” Current Opinion in Investigational Drugs, vol. 10, no. 1, pp. 23–34, 2009. View at Scopus
  241. S. Zelivianski, M. Spellman, M. Kellerman et al., “ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cells,” International Journal of Cancer, vol. 107, no. 3, pp. 478–485, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  242. H. H. Yong, J. M. Hwa, B. R. You et al., “The MEK inhibitor PD98059 attenuates growth inhibition and death in gallic acid-treated Calu-6 lung cancer cells by preventing glutathione depletion,” Molecular Medicine Reports, vol. 3, no. 3, pp. 519–524, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  243. S. J. Lim, Y. J. Lee, and E. Lee, “p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis,” Oncology Reports, vol. 16, no. 5, pp. 1131–1135, 2006. View at Scopus
  244. S. Karunakaran, U. Saeed, M. Mishra et al., “Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice,” Journal of Neuroscience, vol. 28, no. 47, pp. 12500–12509, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  245. F. C. Barone, E. A. Irving, A. M. Ray et al., “Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia,” Medicinal Research Reviews, vol. 21, no. 2, pp. 129–145, 2001. View at Publisher · View at Google Scholar · View at Scopus
  246. S. Martial, J.-L. Giorgelli, A. Renaudo, B. Derijard, and O. Soriani, “SP600125 inhibits Kv channels through a JNK-independent pathway in cancer cells,” Biochemical and Biophysical Research Communications, vol. 366, no. 4, pp. 944–950, 2008. View at Publisher · View at Google Scholar · View at PubMed
  247. J.-H. Kim, T. H. Kim, H. S. Kang, J. Ro, H. S. Kim, and S. Yoon, “SP600125, an inhibitor of Jnk pathway, reduces viability of relatively resistant cancer cells to doxorubicin,” Biochemical and Biophysical Research Communications, vol. 387, no. 3, pp. 450–455, 2009. View at Publisher · View at Google Scholar · View at PubMed
  248. L. H. Wang, C. G. Besirli, and E. M. Johnson Jr., “Mixed-lineage kinases: a target for the prevention of neurodegeneration,” Annual Review of Pharmacology and Toxicology, vol. 44, pp. 451–474, 2004. View at Publisher · View at Google Scholar · View at PubMed
  249. J. Leszek, A. D. Inglot, M. Janusz et al., “Colostrinin proline-rich polypeptide complex from ovine colostrum—a long-term study of its efficacy in Alzheimer's disease,” Medical Science Monitor, vol. 8, no. 10, pp. PI93–PI96, 2002. View at Scopus
  250. C. Y. Kuan and R. E. Burke, “Targeting the JNK signaling pathway for stroke and parkinson's diseases therapy,” Current Drug Targets, vol. 4, no. 1, pp. 63–67, 2005. View at Publisher · View at Google Scholar · View at Scopus