Confirming whether novel rhein derivative 4a induces paraptosis-like cell death by endoplasmic reticulum stress in ovarian cancer cells.

Ovarian cancer is the leading cause of death among gynecologic cancer patients. Although platinum-based chemotherapy as a frontline treatment for ovarian cancer has been widely used in clinical settings, its clinical efficacy is not satisfactory due to the resistance of ovarian cancer cells to apoptosis. Therefore, it is of great significance to induce non-apoptotic programed cell death patterns, such as paraptosis, in ovarian cancer. In this study, we aimed to explore the potential anticancer mechanisms of novel rhein derivative 4a, which was modified with rhein as a lead compound. The results showed that a wide range of vacuoles from the endoplasmic reticulum and mitochondria appeared in ovarian SKOV3, SKOV3-PM4, and A2780 cells treated with derivative 4a, and the cell death caused by derivative 4a is a type of non-apoptotic and non-autophagic death, which is caused by expansion and damage of the endoplasmic reticulum or mitochondria, showing the characteristics of para-apoptotic death. Furthermore, derivative 4a stimulated the unfolded protein reaction of ovarian cancer cells by upregulating the expression of Bip78 and activating the PERK-eIF2α-ATF4 pathways. Notably, rhein derivative 4a-induced cell death was positively correlated with activation of p38, ERK, and JNK, and negatively correlated with Alix, a known protein that inhibits paraptosis. In addition, derivative 4a treatment also induced G2/M phase arrest in ovarian cancer cells. Taken together, our study reveals that derivative 4a induces paraptosis, and this finding can serve as a basis in developing a new strategy for the treatment of antiapoptotic ovarian cancer.

[Effects of wogonin on inducing apoptosis of human ovarian cancer A2780 cells and telomerase activity].

BACKGROUND & OBJECTIVE: Inducing apoptosis and inhibiting the telomerase activity of tumor cells became a new therapeutic means for tumor. In vivo and in vitro experiments showed that wogonin possesses antioxidant activities and inhibitory effect on tumor cells growth. This study was designed to evaluate the effect of wogonin on telomerase activity and apoptosis of human ovarian carcinoma cell line A2780. METHODS: MTT assay,fluorescent microscopy,and DNA agarose gel electrophoresis were used to determine the role of wogonin on apoptosis of A2780 cells. The telomerase activity of A2780 cells were observed by using TRAP-ELASA method. RESULTS: A2780 cell growth was significantly inhibited by wogonin. The inhibiting effect showed concentration-dependent and time-dependent manners with IC(50) of 85 microg/ml. After treatment with 50 microg/ml and 100 microg/ml wogonin for 48 hours, A2780 cells showed morphological changes associated with the characters of apoptosis under fluorescent microscope. Typical DNA ladder was found using agarose gel electrophoresis. Telomerase activity of A2780 cells was gradually decreased with the increasing of wogonin concentration. When the concentration of wogonin was higher than 200 microg/ml, telomerase activity of A2780 cells was inhibited markedly. CONCLUSION: Wogonin can inhibit proliferation and induce apoptosis of A2780 cells within a certain concentration range(50-250 microg/ml). Anticancer effects of wogonin were associated with the induction of apoptosis and partly with the suppression of telomerase activity.