Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells

Abstract

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.

Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway

“…Previously, we demonstrated that solamargine increases the expression of tumor necrosis factor receptors (TNFR1 and TNFR2) [6,[8][9][10], along with activation of the mitochondrial pathway of apoptosis, in human hepatocellular carcinoma (HepG2 and Hep3B), lung cancer cells (A549, H441, H520, H661 and H69) [11,12], and breast cancer (SK-BR3, MCF-7, HBL-100 and ZR-75-1) cell lines [13]. Compared with paclitaxel, cisplatin, gemcitabine and etoposide, solamargine was found to have a superior effect in suppressing human lung cancer cell growth [12].…”

“…100 other Solanum species [6]. S. incanum extract is an important traditional Chinese medicine in Taiwan for the treatment of various chronic liver diseases since 1973.…”

Efficacy and Safety of <i>Rhus verniciflua</i> Stokes Extracts in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer

“…As a result, the search for new therapeutic strategies is motivated not only by the need to improve survival rates, but also by the desire to reduce toxicity, decrease symptoms, and improve the quality of life of this patient population. There have been several pervious reports evaluating the efficacy of herbal medicine, but most were tested in vitro only and only poorly defined the characteristics of patients and primary cancers [17,18,[32][33][34][35].…”

Are there new therapeutic options for treating lung cancer based on herbal medicines and their metabolites?

“…SM enhanced the cytotoxicity against human lung cancer H661 and H69 cells to trastuzumab and epirubidin (Liang et al, 2008). Furthermore, SM sensitized apoptosis induction in tumor necrosis factor (TNF) and cisplatin-resistant lung cancer cells (Liang et al, 2004) and combination therapy of SM and epirubicin effectively promoted chemotherapy-induced apoptosis in A549 cells (Liang et al, 2007), strongly suggesting the potential of SM as a MDR reversal agent. Additional bioactive phytochemicals were reported as potent MDR reversal agents; a novel monoketone curcumin analog, EF24 from Curcuma longa (Zingiberaceae) (Thomas et al, 2010), emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) from Rheum palmatum (Polygonaceae) (Ko et al, 2010), and ␤-elemene from Curcuma kwangsiensis (Zingiberaceae) (Zhao et al, 2007).…”