Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy.
Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells.
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Xue
X
Feng
Department of Brain Cognition Computing Lab, University of Kent, Kent CT2 7NZ, UK.
Ling
L
Li
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Hong
H
Jiang
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Keping
K
Jiang
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Ye
Y
Jin
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: zhengjianhua1115@126.com.
Jianhua
J
Zheng
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D037621:Artemisinins; C039060:artenimol; D002945:Cisplatin
Apoptosis; Autophagy; Cisplatin; Dihydroartemisinin; Ovarian cancer; mTOR