Rubus coreanus Miquel extract causes apoptosis of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation

Cancer cells can acquire an anticancer, drug-resistant phenotype following chemotherapy, which is tightly linked to cancer malignancy and patient survival rates. Therefore, the identification of options to treat chemotherapy-resistant cancer cells is an urgent requirement. Rubus coreanus Miquel (RCM) has long been used as a source of food. In addition, it has been reported that RCM has effective functions against particular diseases, including cancer and inflammation. In the present study, it was demonstrated that RCM extract caused the apoptotic cell death of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells by phosphorylating c-Jun N-terminal kinase (JNK). The RCM-mediated reduction of cell viability showed no synergism with doxorubicin. In addition, ellagic acid and quercetin, which are phytochemicals found in RCM, also caused apoptosis of the NCI/ADR-RES cells. In subsequent investigations of the RCM-altered signaling pathway, RCM extract, ellagic acid and quercetin were found to commonly induce the phosphorylation of JNK and AKT. Additionally, the inhibition of JNK with SP600125 repressed the apoptotic cell death induced by RCM extract, ellagic acid and quercetin, and the inhibition of JNK appeared to switch apoptosis to necrosis. JNK inhibition also reduced the phosphorylation of AKT, which was induced by RCM extract, ellagic acid and quercetin, suggesting that the phosphorylation of JNK is required for AKT phosphorylation in RCM-, ellagic acid- or quercetin-induced apoptotic cell death. Therefore, the data obtained in the present study led to the conclusion that RCM caused apoptosis of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation, and suggested that RCM may be effective in the treatment of chemotherapy-resistant cancer cells.