Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling
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Xu-Wei Zhou1,*, Yuan-Zheng Xia1,*, Ya-Long Zhang1, Jian-Guang Luo1, Chao Han1, Hao Zhang1, Chao Zhang1, Lei Yang1 and Ling-Yi Kong1
1Jiangsu 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
Lei Yang, email: email@example.com
Ling-Yi Kong, email: firstname.lastname@example.org
Keywords: tomentodione M; meroterpenoid; multidrug resistance; P-glycoprotein; p38
Received: July 02, 2017 Accepted: October 03, 2017 Published: October 19, 2017
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.
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