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.