Capsaicin Acts Through Reducing P38 MAPK-Dependent Thymidylate Synthase Expression to Enhance 5-Fluorouracil-Induced Cytotoxicity in Human Lung Cancer Cells

Capsaicin, an ingredient of green and red bell peppers, shows anticancer activity in several malignant cell lines. Thymidylate synthase (TS) is a well-validated anticancer drug target in non-small cell lung cancer (NSCLC) cells. However, whether capsaicin and 5-fluorouracil (5-FU) induce synergistic cytotoxicity in NSCLC cells by regulating TS expression is unclear. This study investigated the cytotoxicity of capsaicin and 5-FU co-treatment on two hoursuman lung adenocarcinoma cell lines, H520 and H1703, and the underlying mechanisms. Capsaicin decreased TS expression in a p38 mitogen-activated protein kinase (MAPK) inactivation–dependent manner in H520 and H1703 cells. Enhancement of p38 MAPK activity by transfection with constitutive active mitogen-activated protein kinase kinase six vectors increased TS expression and cell survival. In addition, capsaicin and 5-FU co-treatment enhanced synergistic cytotoxicity and inhibited cell growth associated with TS downregulation and p38 MAPK inactivation in H520 and H1703 cells. Capsaicin and 5-FU co-treatment did not affect the cellular content of capsaicin. These results show that capsaicin may be combined with 5-FU to treat NSCLC.