Research Article | Open Access
WeiHua Yin, GuPing Zhong, HuiZhen Fan, HongMei Xia, "The Effect of Compound Sophora on Fluorouracil and Oxaliplatin Resistance in Colorectal Cancer Cells", Evidence-Based Complementary and Alternative Medicine, vol. 2019, Article ID 7564232, 8 pages, 2019. https://doi.org/10.1155/2019/7564232
The Effect of Compound Sophora on Fluorouracil and Oxaliplatin Resistance in Colorectal Cancer Cells
Fluorouracil (5-FU) and oxaliplatin (L-OHP) are the most commonly used chemotherapy drugs for colorectal cancer, though resistance is common. Compound Sophora injection is a traditional Chinese medicine that can protect the liver against oxidation, improve immunity, and enhance sensitivity to chemotherapy; it may have an effect of reversing resistance in 5-FU- and L-OHP-resistant gastric cancer cells (5-FU/SW480 and L-OHP/SW480, respectively). A concentration gradient experiment was performed to identify a nontoxic dose of compound Sophora injection. 5-FU/SW480 and L-OHP/SW480 cells were treated with the nontoxic dose of compound radix Sophorae injection for 48 h, and changes in drug resistance to 5-FU and L-OHP were detected. Alterations in apoptosis and the cell cycle were assessed, as were the mRNA and protein levels of permeability glycoprotein (P-gp), annexin A1 (ANXA1), and ATP-binding cassette superfamily G member 2 (ABCG2). Flow cytometry showed a reduction in the number of cells in the G1 phase and an increase of cells in the S phase (). mRNA and protein expression of P-gp and ABCG2 was significantly higher in 5-FU/SW480 and L-OHP/SW480 cell lines, and ANXA1 expression decreased significantly (). Compound Sophora injection can reverse the drug resistance of 5-FU/SW480 and L-OHP/SW480 cell lines to 5-FU and L-OHP, respectively, possibly through a mechanism involving reduced expression of P-gp and ABCG2 but enhanced expression of ANXA1, which is the basis for the identification of clinical drug resistance in colorectal cancer.
In recent years, the incidence of colorectal cancer has increased annually worldwide, becoming one of the most common malignant tumours. The incidence of colorectal cancer ranks third of all malignant tumours, and the fatality rate ranks fifth [1, 2]. Chemotherapy is a common treatment for colorectal cancer, though multidrug resistance (MDR) in tumors often leads to treatment failure. MDR (also known as multidrug hold) occurs when a tumour cell develops antitumour drug resistance, in which different chemical structures exert different actions. Different antitumour drugs also produce cross-resistance [3, 4]. Abnormal expression of drug-resistance proteins such as permeability glycoprotein (P-gp), annexin A1 (ANXA1), and ATP-binding cassette superfamily G member 2 (ABCG2) have been found in colorectal tumour tissues of patients with primary MDR, resulting in different levels of drug resistance to chemotherapy drugs in tumour cells [5–7]. Therefore, the search for effective drugs to reverse MDR has become a hot topic in the treatment of colorectal cancer, and an increasing number of researchers are paying attention to traditional Chinese medicine due to extensive advantages of low toxicity, high efficiency, and multitarget function . Indeed, studies to date have shown the potential for the development of traditional Chinese medicine to treat tumour MDR. Compound radix Sophorae injection is a traditional Chinese medicine that exerts antioxidant effects, protects the liver, enhances immunity, and provides chemotherapeutic sensitivity [9–11]. The injection is prepared from extracts of radix Sophora flavescens, poriacocoscocos, and pachycocoscocos, and the main effective components are oxymatrine, sophorine, and matrine. Rasul et al. showed that compound matrine injection and its components, such as matrine and oxymatrine, had direct killing effects on various tumour cells, such as SGC-7901, HepG2, and BEL-7402, and could inhibit the invasion and metastasis of gastric cancer SGC-7901 cells [12–14]. Oxymatrine inhibits the proliferation of vascular endothelial cells . In general, compound radix Sophora flavescens injection has been found to have a good antitumour effect in clinical applications. Combined chemotherapy can effectively reduce or stabilize the tumours, improve quality of life, and significantly alleviate pain due to cancer . Compound Sophora injection has occasional adverse reactions to rashes in the clinic [16, 17]. However, it is not clear whether compound Sophora injection can reverse the resistance. In this study, the effects of compound Sophora injection on the expression of P-gp, ANXA1, ABCG2, and other drug-resistance proteins in drug-resistant colorectal cancer cell lines (fluorouracil (5-FU)/SW480 and oxaliplatin (L-OHP)/SW480) were studied [5–7], as were its effects on MDR, and the reversal mechanism was examined.
2. Materials and Methods
The colorectal cancer cell line SW480 was purchased from American Type Culture Collection (ATCC). 5-FU and L-OHP were both produced by Jiangsu Hengrui Pharmaceutical Co., Ltd. The compound radix Sophorae injection was obtained from Shanxi Zhendong Pharmaceutical Co., Ltd. The RPMI-1640 medium was purchased from GIBCO (Thermo Fisher Scientific, Inc., Waltham, MA, USA).
2.1.1. Resistant Strains
Resistant strains were induced by a short-term method. At the logarithmic growth stage, most SW480 cells died after 1 h of incubation with 5-FU and L-OHP. The RPMI-1640 medium was added to the cells, which were washed twice with RPMI-1640 and further cultured. When the SW480 cells were again in the logarithmic growth phase, 5-FU or L-OHP was added for 1 h and the induction was repeated. After 8 months, the SW480 cell lines could be grown in the RPMI-1640 medium containing 5-FUor L-OHP, and a single-cell suspension of SW480 5-FU and L-OHP colorectal cancer cell substrains (5-FU/SW480 and L-OHP/SW480, respectively) was obtained. The resistance indexes of 5-FU and L-OHP were 24.26 and 25.31, respectively, as detected by the MTT assay.
2.1.2. Reversal Experiments
At the logarithmic growth stage, 5-FU/SW480 and L-OHP/SW480 drug-resistant cells were inoculated into 96-well plates at a density of 1 × 105 cells per well. After the cells had adhered to the plate, 20 μL, 10 μL, 5 μL, 2.5 μL, or 1.25 μL of compound bitter ginseng injection was added to a final volume of 20 μL. Next, 0 μL, 10 μL, 15 μL, 17.5 μL, and 18.75 μL of PBS was added. The following control groups were established: no addition, blank control, solvent control, and drug (5-FU and L-OHP; positive control). The cells were cultured at 37°C in a 5% CO2 incubator for 48 h. To calculate the inhibitory rate, a concentration-inhibitory rate curve was generated by the MTT assay. The 50% inhibitory concentration (IC50) of compound radix Sophorae injection for 5-FU/SW480 and L-OHP/SW480 cells after 48 h of treatment was calculated as the nontoxic dose to reverse drug resistance. The IC50 values of 5-FU/SW480 and L-OHP/SW480 cells not treated with compound radix Sophorae injection were compared with those treated with the chemotherapy drugs. The drug resistance reversal multiple was calculated, where the reversal multiple is the value of IC50 without reversal divided by the value of IC50 after reversal.
2.1.3. Apoptosis and the Cell Cycle
The drug-resistant strains in the logarithmic growth phase were inoculated into a 24-well cell culture plate. After the cells had adhered to the plate, RPMI-160 medium containing 5-FU and L-OHP was added. At the same time, the negative control group was prepared. After 48 h, 0.25% trypsin (without EDTA) was used to digest and collect the cells. Cells from each treatment group were collected by centrifugation, and annexin V and propidium iodide (PI) double staining was performed according to the manufacturer’s instructions. Flow cytometry was also performed. A single-cell suspension was prepared with 70% ethanol, fixed for 2 h at 4°C, and incubated with 100 μL of RNase A at 37°C for 30 min. Then, 400 μL of PI stain was added and mixed, and the cells were placed in the dark at 4°C for 30 min. The cell cycle was examined by recording red fluorescence at an excitation wavelength of 488 nm.
2.1.4. mRNA Expression
During logarithmic growth, total RNA from drug-resistant 5-FU/SW480 and L-OHP/SW480 cell lines was extracted with the TRIzol reagent. The extracted RNA (11 μL) (less than 0.25 mg) was transferred to a new RNase-free EP tube, and 1 μL of oligo-dT suspension and 1 μL of dNTP mix (10 mM) were added and incubated at 70°C for 10 min (pyrolysis of the RNA secondary structure). The mixture was incubated on ice for 10 min (to let Oligotex combine with the mRNA), after which 4 μL of 5x first-strand buffer, 1 μL of 0.01 M DTT, 1 µL of RNase inhibitor, and 1 μL of Superscript TMIII RT (invitrogen) were added and incubated at 42°C for 40 min. The mixture was then incubated at 70°C for 15 min, and the reaction was stopped at 94°C for 5 min. Using this cDNA as a template, P-gp, ANXA1, ABCG2, and β-actin were detected by PCR (primers were designed by ourselves and synthesized by Guangzhou Vingjun Company). The reaction conditions were as follows: 94°C for 2 min, 36 cycles of 94°C for 30 s, 58°C for 20 s, and 72°C for 1 min, followed by extension at 72°C for 5 min. The PCR products were examined on 1.0% agarose gel. The primer sequences used for each gene were as follows: β-Actin F: 5′-GAAGTCGGAGTCAACGTATGA-3′, R: 5′-TTATGATGACTTCTTGTGCTA-3’ P-gp F: 5′-ACGTAGTTGGTCCGTGAT-3′, R: 5′-GAGGTTCGCCAGTGGTAC-3’ ANXA1 F: 5′-CCACAACTTCGCAGAGTG-3′, R: 5′-CAGAACGGAGACGCATAA-3’ ABCG2 F:5′-CATGGTGTATAGACGCCTGAC-3′, R: 5′-GTCCATATGATGTTGATGACG-3’
2.1.5. Drug-Resistance Proteins
On the basis of the above experiments, the cells were digested with trypsin and then fully lysed with prechilled lysis buffer. Next, 10% SDS-PAGE was performed, and electrophoresis was stopped when the dye front entered the optimal separation zone (approximately 2/3 of the gel). The proteins were transferred to a nitrocellulose (NC) membrane for 90 min, and the membrane was marked. The membrane was blocked in 5% skim milk and washed with TBST, and the appropriate primary antibody (against P-gp, 1 : 250; ANXA1, 1 : 1 000; or ABCG2, 1 : 400) was added and incubated at 4°C overnight with oscillation. After washing, the secondary antibody (1 : 500) (in 5% skim milk) was added and incubated for 2 h at room temperature on a shaking table. One drop of DAB concentrate per 2 mL of 0.02 M PBST was added, followed by 30% H2O2 (final concentration 0.03%) at a ratio of 1 : 1000. The reagents were mixed and added to the membrane, and the membrane was washed with distilled water after colour development to a satisfactory degree. Images were then obtained.
2.2. Statistical Methods
SPSS 13.0 software was used for statistical analysis. Each data point is expressed as the mean ± SD. A 2-sample t-test or a rank-sum test was used to compare the data, and Student’s t-test or analysis or variance was applied to compare measurement data. was considered statistically significant.
3.1. Inhibitory Effect of Compound Radix Sophorae
5-FU/SW480 and L-OHP/SW480 drug-resistant cell strains were inoculated into 96-well plates at a density of 1 × 105 cells per well. After adherence, 20 μL, 10 μL, 5 μL, 2.5 μL, and 1.25 μL of compound radix Sophorae injection was added. Figure 1 shows that inhibition rates for the 5-FU/SW480 and L-OHP/SW480 cells rose with the increase in the concentration of compound radix Sophorae injection, and this inhibition correlated positively with the drug concentration. SPSS 13.0 software was used to calculate the IC50 values of 5-FU/SW480 and L-OHP/SW480 cells 48 h after compound radix Sophorae injection, which were 0.84 and 0.89 g/mL, respectively. These concentrations were used as nontoxic doses to reverse drug resistance.
3.2. Reversal Ability of Compound Radix Sophorae
The IC50 value of 5-FU to 5-FU/SW480 cells was 5.41 ± 0.12 g/mL, and the IC50 value of L-OHP to L-OHP/SW480 cells was 6.15 ± 0.24 g/mL. The IC50 values of 5-FU and L-OHP for the corresponding drug-resistant cells were 2.62 ± 0.18 g/mL and 3.13 ± 0.14 g/mL, respectively, after the addition of nontoxic doses of compound radix Sophora flavescens injection (0.84 and 0.89 g/mL, respectively). The IC50 values decreased (), and the drug resistance reversion multiples were 2.07 and 1.97, respectively. This result indicated that compound radix Sophorae root injection had a drug resistance reversal effect on 5-FU/SW480 and L-OHP/SW480 cells.
3.3. Analysis of Apoptosis and the Cell Cycle
Cell cycle analysis was performed on 5-FU/SW480 and L-OHP/SW480 cells, which served as control groups. The numbers of 5-FU/SW480 and L-OHP/SW480 cells treated with compound bitter ginseng injection in the G1 phase were decreased compared with the control group, whereas the number of cells in S and G2 phases were significantly increased (; Table 1). Apoptosis increased slightly in 5-FU/SW480 and L-OHP/SW480 cells, though the difference was not significant (; Figure 2).
3.4. mRNA Detection in Drug-Resistant Strains
The mRNA expression levels of P-gp and ABCG2 in 5-FU/SW480 and L-OHP/SW480 cells were significantly decreased after the addition of a nontoxic dose of compound radix Sophorae injection. However, ANXA1 expression increased significantly (), as shown in Figure 3.
3.5. Drug-Resistance Protein Expression Detection
Western blot analysis was used to detect the expression levels of related proteins. Without the addition of a nontoxic dose of compound bitter ginseng injection, the expression levels of P-gp and ABCG2 in the 5-FU/SW480 and L-OHP/SW480 cell lines were increased. But the expression levels of ANXA1 decreased significantly (; Figure 4).
Chemotherapy is an important means of treating colorectal cancer, but many patients show MDR during the course of chemotherapy, which is the main reason for treatment failure [3, 4]. Chemotherapy for colorectal cancer consists mostly of three drugs, 5-FU, oxaliplatin. and irinotecan, which are combined in clinical practice , but treatment is difficult if resistance occurs . Traditional Chinese medicine is expected to be an ideal agent for reversing MDR after the failure of chemotherapy for tumours due to its low toxicity, good stability, and unique effects [8, 9, 19]. In fact, identification of a Chinese medicine preparation that is sensitive, reduces toxicity, shows synergistic and complementary effects with drugs, and reduces drug resistance is urgently needed. Compound Sophorae Flavescentis injection is a traditional Chinese medicine that has antioxidant and antitumour properties and improves immunity [10, 20]. In the treatment of colorectal cancer, compound radix Sophorae injection, which can reduce the toxicity and side effects of chemotherapy drugs, improves the short-term efficacy of chemotherapy and the quality of life of patients . Our preliminary research reveals that it can also reduce the toxicity and side effects of drugs and radiotherapy for colorectal cancer and has certain sensitizing functions for radiotherapy and chemotherapy in the treatment of colorectal cancer.
Chemotherapy resistance is a very common phenomenon in patients with colorectal cancer. It is believed that the mechanism of MDR involves two aspects:(1) membrane glycoproteins, energy-dependent drug efflux pumps that can reduce the concentrations of drugs in the cell or form a compartmentalized distribution, resulting in drug resistance, including P-gp, ABCG2, and MRP [5, 21], and (2) enzyme-mediated resistance (e.g., topoisomerase (toPo), glutathione transferase (GST), and protein kinase C (PKc)or abnormal expression of apoptotic regulatory genes, though antitumour drugs mainly play a role by inducing apoptosis). Among these factors, the Bcl-2 family, p53, and c-myc are involved in resistance [22, 23]. Compound radix Sophorae injection has antioxidant ability, enhances the function of GST and regulates the caspase pathway to induce apoptosis. Therefore, compound radix Sophorae root injection has a certain effect of reversing MDR in chemotherapy, and its mechanism is related to inhibition of the expression of the drug-resistance protein P-gp. This study showed that the IC50 values of 5-FUin 5-FU/SW480 cells and L-OHP in L-OHP/SW480 cells were 5.41 ± 0.12 g/mL and 6.15 ± 0.24 g/mL, respectively, with drug resistance reversion multiples 2.07 and 1.97, respectively. Thus, compound radix Sophorae root injection had a certain drug resistance reversal effect on 5-FU/SW480 and L-OHP/SW480 cells. Compound radix Sophorae root injection induces tumour cell apoptosis, which is one of the mechanisms for reversing drug resistance. ANXA1 is the first member of the family of membrane-linked proteins that inhibits the transcription of nuclear factor kappa B (NF-κB) by blocking its binding to DNA, thereby inhibiting the proliferation of tumour cells and promoting their apoptosis . Therefore, it is believed that the downregulated expression level of ANXA1 in drug-resistant cell lines leads to a decrease in tumour cell apoptosis, which further reduces the sensitivity of tumour cells to drugs and leads to resistance . Our apoptosis (cell cycle) experiments showed that a nontoxic dose of compound radix Sophorae injection reduced the number of cells in the G1 phase, significantly increased the number of cells in the S phase, significantly increased ANXA1 expression, and slightly increased the rate of apoptosis following treatment, though the difference was not significant (), as shown in Figure 2.
Resistance genes and proteins are an important reason for the occurrence of drug resistance in tumour cells, and P-gp and ABCG2 are the most common proteins in this regard. The dependence of ATP is due to cell membrane transporters, which are energy-dependent drug efflux pumps that can actively pump drugs out of tumour cells. This process reduces the drug concentration or compartment distribution and results in a decline in the effective concentration of the drug in the cells, prompting them to develop properties of resistance . The ABC transporter can transport drugs from the cytoplasm to the extracellular environment using the energy from ATP hydrolysis . Studies have confirmed that ABCG2 is closely related to the drug resistance of breast cancer and nonsmall cell lung cancer [27–29]. At present, researchers believe that P-gp and ABCG2 can pump most chemotherapy drugs out of the cell, resulting in a reduction in the intracellular drug concentration and showing that tumour cells possess extensive drug resistance mechanisms, namely, MDR . The results of this study showed that the 5-FU/SW480 and L-OHP/SW480 drug-resistant cell lines mainly developed chemical drug resistance by upregulating expression of P-gp, ABCG2, and other drug-resistance proteins. However, compound radix Sophorae injection reversed drug resistance in these cells by downregulating expression of P-gp, ABCG2, and other drug-resistance proteins.
In summary, compound radix Sophorae injection can reverse the resistance of 5-FU/SW480 and L-OHP/SW480 drug-resistant cells to 5-FU and L-OHP, respectively, and the reversal mechanism may be related to the expression of drug-resistance proteins, such as P-gp. Therefore, compound radix Sophorae injection can reduce the occurrence of drug resistance in colorectal cancer cells, increase the sensitivity of tumours to chemotherapy drugs, and effectively increase the short-term clinical effective rate among patients with drug-resistant tumours, which is worthy of clinical promotion.
All data supporting the findings of this study are included in this article.
Conflicts of Interest
The authors declare no conflicts of interest.
Weihua Yin conceptualized and designed the experiments. Hongmei Xia, HuiZhen Fan and Guo Ping Zhong performed all of the experiments. Huizhen Fan analysed the data. Hongmei Xia and Weihua Yin wrote the manuscript.
This work was supported by the Natural Science Foundation of China (no. 81360606) and Project of Jiangxi Health and Health Commission (no. 20161861).
- W. A. Messersmith, “Systemic management of colorectal cancer,” Journal of the National Comprehensive Cancer Network: JNCCN, vol. 15, no. 5S, pp. 699–702, 2017.
- A. B. Benson, A. P. Venook, L. Cederquist et al., “Colon cancer, version 1.2017, NCCN clinical practice guidelines in oncology,” Journal of the National Comprehensive Cancer Network: JNCCN, vol. 15, no. 3, pp. 370–398, 2017.
- E. Mungo, L. Bergandi, I. C. Salaroglio, and S. Doublier, “Pyruvate treatment restores the effectiveness of chemotherapeutic agents in human colon adenocarcinoma and pleural mesothelioma cells,” International Journal of Molecular Sciences, vol. 19, no. 11, p. 3550, 2018.
- C. Zhang, L. J. He, H. Z. Ye et al., “Nrf2 is a key factor in the reversal effect of curcumin on multidrug resistance in the HCT-8/5-Fu human colorectal cancer cell line,” Molecular Medicine Reports, vol. 18, no. 6, pp. 5409–5416, 2018.
- M. Cantore, E. Capparelli, F. Berardi, R. Perrone, and N. A. Colabufo, “Clinical pharmacokinetic and metabolism of PET radiotracers for imaging P-glycoprotein in chemoresistant tumor of colorectal cancer,” Current Drug Metabolism, vol. 12, no. 10, pp. 985–988, 2011.
- H. Onozawa, M. Saito, K. Saito et al., “Annexin A1 is involved in resistance to 5-FU in colon cancer cells,” Oncology Reports, vol. 37, no. 1, pp. 235–240, 2017.
- M.-C. Chen, H.-H. Hsu, Y.-Y. Chu et al., “Lupeol alters ER stress-signaling pathway by downregulating ABCG2 expression to induce oxaliplatin-resistant LoVo colorectal cancer cell apoptosis,” Environmental Toxicology, vol. 33, no. 5, pp. 587–593, 2018.
- L. Ge, Y.-F. Wang, J.-H. Tian et al., “Network meta-analysis of Chinese herb injections combined with FOLFOX chemotherapy in the treatment of advanced colorectal cancer,” Journal of Clinical Pharmacy and Therapeutics, vol. 41, no. 4, pp. 383–391, 2016.
- D. Zhang, J. Wu, X. Duan et al., “Network meta-analysis of Chinese herbal injections plus the FOLFOX regimen for the treatment of colorectal cancer in China,” Integrative Cancer Therapies, vol. 18, 2019.
- L. Gao, K.-X. Wang, Y.-Z. Zhou, J.-S. Fang, X.-M. Qin, and G.-H. Du, “Uncovering the anticancer mechanism of compound kushen injection against HCC by integrating quantitative analysis, network analysis and experimental validation,” Scientific Reports, vol. 8, no. 1, p. 624, 2018.
- W. Wang, R.-L. You, W.-J. Qin et al., “Anti-tumor activities of active ingredients in compound kushen injection,” Acta Pharmacologica Sinica, vol. 36, no. 6, pp. 676–679, 2015.
- A. Rasul, B. Yu, L. F. Yang et al., “Induction of mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells by kuraridin and nor-kurarinone isolated from sophora flavescens,” Asian Pacific Journal of Cancer Prevention: APJCP, vol. 12, no. 10, pp. 2499–2504, 2011.
- H. Li, S. Xie, X. Liu et al., “Matrine alters microRNA expression profiles in SGC-7901 human gastric cancer cells,” Oncology Reports, vol. 32, no. 5, pp. 2118–2126, 2014.
- Z. Li, L. Zheng, J. Shi et al., “Toxic markers of matrine determined using (1) H-NMR-based metabolomics in cultured cells in vitro and rats in vivo,” Evidence-based Complementary and Alternative Medicine, vol. 2015, Article ID 598412, 11 pages, 2015.
- M. Xie, G. He, R. Wang et al., “Matrine-induced apoptosis of human nasopharyngeal carcinoma cells via in vitro vascular endothelial growth factor-A/extracellular signal-regulated kinase1/2 pathway inactivation,” Hormone and Metabolic Research, vol. 46, no. 8, pp. 556–560, 2014.
- M. Chen, B. H. May, I. W. Zhou, C. C. L. Xue, and A. L. Zhang, “FOLFOX 4 combined with herbal medicine for advanced colorectal cancer: a systematic review,” Phytotherapy Research: PTR, vol. 28, no. 7, pp. 976–991, 2014.
- X. Yang, W. Cai, Q. Yang, Z. Lu, J. Li, and J. Yu, “Compound radix sophorae flavescentis exerts antitumor effects by inhibiting the proliferation and inducing the apoptosis of esophageal carcinoma TE-8 cells,” Oncology Letters, vol. 10, no. 4, pp. 2209–2213, 2015.
- L. Rimassa, S. Bozzarelli, F. Pietrantonio et al., “Phase II study of tivantinib and cetuximab in patients with KRAS wild-type metastatic colorectal cancer with acquired resistance to EGFR inhibitors and emergence of MET overexpression: lesson learned for future trials with EGFR/MET dual inhibition,” Clinical Colorectal Cancer, vol. 18, no. 2, pp. 125–132.e2, 2019.
- J. Cui, Z. Qu, Y. Harata-Lee et al., “Cell cycle, energy metabolism and DNA repair pathways in cancer cells are suppressed by compound kushen injection,” BMC Cancer, vol. 19, no. 1, p. 103, 2019.
- L. Wu, G. Wang, S. Liu et al., “Synthesis and biological evaluation of matrine derivatives containing benzo-α-pyrone structure as potent anti-lung cancer agents,” Scientific Reports, vol. 6, no. 1, p. 35918, 2016.
- H. Yim and K. Na, “Polycationic nanodrug covered with hyaluronic acid for treatment of P-glycoprotein overexpressing cancer cells,” Biomacromolecules, vol. 11, no. 9, pp. 2387–2393, 2010.
- C.-W. Fan, C.-C. Chan, C.-C. Chao, H.-A. Fan, D.-L. Sheu, and E.-C. Chan, “Expression patterns of cell cycle and apoptosis-related genes in a multidrug-resistant human colon carcinoma cell line,” Scandinavian Journal of Gastroenterology, vol. 39, no. 5, pp. 464–469, 2004.
- Y. Wang, X. Liu, J. Liu, and T. Zhang, “Knockdown of REG Iα enhances the sensitivity to 5-fluorouracil of colorectal cancer cells via cyclin D1/CDK4 pathway and BAX/BCL-2 pathways,” Cancer Biotherapy & Radiopharmaceuticals, vol. 34, no. 6, pp. 362–370, 2019.
- B. Liu, T. Xu, X. Xu, Y. Cui, and X. Xing, “Biglycan promotes the chemotherapy resistance of colon cancer by activating NF-κB signal transduction,” Molecular and Cellular Biochemistry, vol. 449, no. 1-2, pp. 285–294, 2018.
- G. E. do Imperio, E. Bloise, M. Javam et al., “Chorioamnionitis induces a specific signature of placental ABC transporters associated with an increase of miR-331-5p in the human preterm placenta,” Cellular Physiology and Biochemistry, vol. 45, no. 2, pp. 591–604, 2018.
- M. P. Ceballos, J. P. Rigalli, L. I. Cere, M. Semeniuk, V. A. Catania, and M. L. Ruiz, “ABC transporters: regulation and association with multidrug resistance in hepatocellular carcinoma and colorectal carcinoma,” Current Medicinal Chemistry, vol. 26, no. 7, pp. 1224–1250, 2019.
- M. Vesel, J. Rapp, D. Feller et al., “ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling,” Respiratory Research, vol. 18, no. 1, p. 52, 2017.
- G.-N. Zhang, Y.-K. Zhang, Y.-J. Wang et al., “Epidermal growth factor receptor (EGFR) inhibitor PD153035 reverses ABCG2-mediated multidrug resistance in non-small cell lung cancer: in vitro and in vivo,” Cancer Letters, vol. 424, pp. 19–29, 2018.
- A. Arumugam, R. Subramani, S. B. Nandy et al., “Silencing growth hormone receptor inhibits estrogen receptor negative breast cancer through ATP-binding cassette sub-family G member 2,” Experimental & Molecular Medicine, vol. 51, no. 1, p. 2, 2019.
- A. Sorf, J. Hofman, R. Kučera, F. Staud, and M. Ceckova, “Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro,” Biochemical Pharmacology, vol. 154, pp. 10–17, 2018.
Copyright © 2019 WeiHua Yin et al. 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.