Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells.
Nonsmall-cell lung cancer (NSCLC) is not generally a chemosensitive tumor, and the mechanism of resistance to the relevant anticancer drugs has not been fully elucidated. Solamargine (SM), the major steroidal glycoalkaloids extracted from the Chinese herb Solanum, inhibits the growth of human tumor cells. We have previously demonstrated that SM regulates tumor necrosis factor receptors (TNFRs)- and mitochondria-mediated pathways and sensitizes NSCLC cells to initiate apoptosis. Interestingly, this investigation reveals that SM up-regulated Fas expression and down-regulated the expression of HER2, whose overexpression is associated with resistance to drugs, and promotes chemotherapy-induced apoptosis in NSCLC A549 and H441 cells. After treatment with SM, the expression of HER2 mRNA was correlated with the expression of topoisomerase IIalpha (TOP2A) mRNA. The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death. Therefore, the downregulation of the HER2 and TOP2A expression by SM with epirubicin may partially explain the SM and epirubicin cytotoxicity synergy effect in NSCLC. Results of this study suggest that SM induces Fas and TNFR-induced NSCLC cell apoptosis and reduces HER2 expression. These findings provide the synergistic therapeutic interaction between SM and epirubicin, suggesting that such combinations may be effectively exploited in future human cancer clinical trials.
Liang
Chia-Hua
CH
Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Shiu
Li-Yen
LY
Chang
Li-Ching
LC
Sheu
Hamm-Ming
HM
Kuo
Kou-Wha
KW
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D015251:Epirubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000032:analysis; D012991:Solanaceous Alkaloids / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D012991:Solanaceous Alkaloids; D019014:fas Receptor; C026609:beta-solamarine; D015251:Epirubicin; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human