Norcantharidin, Derivative of Cantharidin, for Cancer Stem Cells
Table 1
Summary of norcantharidin (NCTD) against human cancer stem cells (CSCs) and cancer cells.
Target class
Target demonstrated
Effects and mechanisms
Comments
References
Stem cells
*Hepatic leukemia factor (HLF) protein levels, a gene implicated in hematopoietic stem cell (HSCs). *Acute myeloid leukemia (AML) cell line MV4-11.
*NCTD decreased HLF protein levels, a gene implicated in hematopoietic stem cell (HSCs) regulation. *NCTD induced apoptosis in the AML cell line MV4-11 by modulating the expression of molecules that govern survival pathway, including HLF, SLUG, NFIL3, and c-myc, inducing p53 and the mitochondrial caspase cascade
Explores the ability of NCTD to target stem cells.
NCTD downregulates expression of desmoglein, N-cadherin, and alpha- and beta-catenin, while there were no obvious changes in E-cadherin and gamma-catenin in colorectal cancer CT26 cells.
NCTD is effective in blocking both tumor invasion and metastasis.
The activation of Wnt target genes: c-Jun and cyclin D1
Human gallbladder carcinoma GBC-SD cells xenografted tumors
NCTD inhibits the growth of the xenografted tumors in a dose- and time-dependent manner and decreases the expression of cyclin-D1, Bcl-2, and survivin proteins/mRNAs significantly.
NCTD inhibits the growth of xenografted tumors of human gallbladder carcinoma in nude mice by inducing apoptosis and blocking the activation of Wnt target genes, cyclin-D1.
NCTD inhibits cell proliferation, arrest of the cell cycle, blockage of DNA synthesis, induction of cell apoptosis and influence on expression of the proliferation-related genes PCNA, Ki-67, cyclin-D1 and p27, and the apoptosis-related genes Bcl-2, Bax, and survivin in human gallbladder carcinoma GBC-SD cells.
NCTD inhibits the growth of human gallbladder carcinoma GBC-SD cells in vitro and decreases the expression of cyclin-D1 in human gallbladder carcinoma GBC-SD cells.
NCTD inhibits migration and capillary-like tube formation of HUVECs. The antiangiogenic effect of NCTD is accompanied by anoikis, downregulation of integrin beta1 and breakdown of vimentin.
NCTD inhibited the release of proangiogenic factors from HUVECs.
Human breast cancer MCF-7 cells, MDA-MB-231 and BT-474 cells
NCTD suppresses the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone.
NCTD overcomes multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.
NCTD downregulates matrix metalloproteinase-9 (MMP-9) expression by inhibiting Sp1 transcriptional activity and suppresses the activation of several cadherin-catenin adhesion molecules of desmoglein, N-cadherin, and alpha- and beta-catenin in colorectal cancer CT26 cells.
NCTD inhibits metastasis in CT26 cells by the downexpression of MMP-9 activity through inhibiting transcriptional activity of Sp1.
The crosstalk between Hedgehog signaling, Wnt/-catenin, notch signaling, and phosphoinositide 3 (PI3)-kinase/Akt pathway
Human breast cancer MDA-MB-231 cells
NCTD induces apoptosis and cell cycle arrest as well as reduction of Bcl-2/Bax ratio that may be the important mechanisms of action of NCTD suppressing the growth of MDA-MB-231 cells, which are associated with inhibition of the Akt and NF-kappa B signaling pathway.
NCTD dose-dependently suppresses the phosphorylation of Akt and NF-κB expression in human breast cancer MDA-MB-231 cells.
Activation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and modulation of downstream transcription factor NF-B are involved in NCTD-induced apoptosis for human hepatoma HepG2 cells
NCTD activates NF-kappa B through Ikappa B kinase (IKK)-dependent phosphorylation pathway for HepG2 cells.
NTCD activates mitogen-activated protein kinases (MAPKs) family member proteins, extracellular signal-regulated kinase (ERK), p38(MAPK), and c-Jun N-terminal kinase (JNK) for breast cancer cells (HS-578T).
NTCD may be an effective anti-cancer drug against breast cancer through MAPK and signal transducers and activators of transcription (STATs) pathways.
NCTD can inhibit ERK1/2 phosphorylation effectively, by reducing NF-κB DNA-binding activities, leading to matrix metalloproteinases (MMP)-9 downregulation and u-plasminogen activator (PA) expression to reduce the invasion of hepatocellular carcinoma (Huh7) cells.
NCTD inhibits MMP-9 and u-PA expression through the phosphorylation of ERK1/2 and NF-kappaB signaling pathway for Huh7 cells.
The absorption rate constants (Ka) of NCTD at different segments were found to be duodenum > jejunum > ileum > colon. The transport of NCTD is found to be inhibited by P-glycoprotein (P-gp) inhibitor.
Human epithelial colorectal adenocarcinoma cells (Caco-2) cell
The inhibitor of P-gp and the multidrug resistance-associated protein 2 (MRAP 2) significantly enhances the uptake amount of lactosyl-norcantharidin (Lac-NCTD).
Lac-NCTD-nanoparticles (NPs) could be the substrate of P-gp and the MRAP 2 for Caco-2 cells.
Human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant)
Oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents. NCTD downregulates the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS.
NCTD may overcome the chemoresistance of oral cancer cells with mutant p53 or elevated Bcl-XL levels.
Doxorubicin-(DOX-) resistant human breast cancer MCF-7R cells
NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulation of the MDR-1 mRNA, P-gp, and BCRP protein expression.
NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp in human breast cancer cells.
