// Xu-Wei Zhou 1, * , Yuan-Zheng Xia 1, * , Ya-Long Zhang 1 , Jian-Guang Luo 1 , Chao Han 1 , Hao Zhang 1 , Chao Zhang 1 , Lei Yang 1 and Ling-Yi Kong 1 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China * These authors have contributed equally to this work Correspondence to: Lei Yang, email: dorothy19802003@gmail.com Ling-Yi Kong, email: cpu_lykong@126.com Keywords: tomentodione M; meroterpenoid; multidrug resistance; P-glycoprotein; p38 Received: July 02, 2017 Accepted: October 03, 2017 Published: October 19, 2017 ABSTRACT In this study, we investigated the mechanism by which tomentodione M (TTM), a novel natural syncarpic acid-conjugated monoterpene, reversed multi-drug resistance (MDR) in cancer cells. TTM increased the cytotoxicity of chemotherapeutic drugs such as docetaxel and doxorubicin in MCF-7/MDR and K562/MDR cells in a dose- and time-dependent manner. TTM reduced colony formation and enhanced apoptosis in docetaxel-treated MCF-7/MDR and K562/MDR cells, and it enhanced intracellular accumulation of doxorubicin and rhodamine 123 in MDR cancer cells by reducing drug efflux mediated by P-gp. TTM decreased expression of both P-gp mRNA and protein by inhibiting p38 MAPK signaling. Similarly, the p38 MAPK inhibitor SB203580 reversed MDR in cancer cells by decreasing P-gp expression. Conversely, p38 MAPK-overexpressing MCF-7 and K562 cells showed higher P-gp expression than controls. These observations indicate that TTM reverses MDR in cancer cells by decreasing P-gp expression via p38 MAPK inhibition.

Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling