ABSTRACT
AIM:To study the cisplatin-sensitization effect and mechanism of tripterygium glycosides on cisplatin-resistant human epithelial ovarian cancer cells (SKOV3/DDP).METHODS:The SKOV3/DDP cells in exponential phase of growth were randomly divided into eight groups:blank control group,10 μg/mL DDP group,50 μg/mL GTW group,800 μg/mL GTW group,3 200 μg/mL GTW group,10 μg/mL DDP + 50 μg/mL GTW group,10 μg/mL DDP + 800 μg/mL GTW group and 10 μg/mL DDP + 3 200 μg/mL GTW group.Cell counting kit 8 and flow cytometry and western blot were used to detect the growth inhibiting rate and apoptosis rate and relative expression of GST-π,MDR1,STAT3,p-STAT3 of SKOV3/DDP cells of every group.RESULTS:DDP and GTW produce an additive effect when used concurrently in inhibiting growth of SKOV3/DDP cells.800 μg/mL GTW or 3 200 μg/mL GTW combined with 10 μg/mL DDP can significantly induce apoptosis of SKOV3/DDP cells and downregulate the expression of p-STAT3 (P ＜ 0.05).CONCLUSION:GTW can significantly enhance sensitivity of SKOV3/DDP cells to DDP.The underlying mechanism may be related with down-regulating the expression of p-STAT3 in STAT3 pathway.
ABSTRACT
BACKGROUND: Clinical use of chemotherapeutic drug, cisplatin is limited by its toxicity and drug resistance. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin, to increase efficacy and reduce its toxicity. Here, we screened 16 medicinal plant extracts from Northeast part of India and found that leaf extract of Zanthoxylum armatum DC. (ZALE) induced cytotoxicity as well as an effect on the increasing of the efficiency of chemotherapeutic drugs (cisplatin, mitomycin C and camptothecin). This work shows detail molecular mechanism of anti-cancer activity of ZALE and its potential for combined treatment regimens to enhance the apoptotic response of chemotherapeutic drugs. RESULTS: ZALE induced cytotoxicity, nuclear blebbing and DNA fragmentation in HeLA cells suggesting apoptosis induction in human cervical cell line. However, the apoptosis induced was independent of caspase 3 activation and poly ADP ribose polymerase (PARP) cleavage. Further, ZALE activated Mitogen-activated protein kinases (MAPK) pathway as revealed by increased phosphorylation of extracellular-signal-regulated kinases (ERK), p38 and c-Jun N-ter-minal kinase (JNK). Inhibition of ERK activation but not p38 or JNK completely blocked the ZALE induced apoptosis suggesting an ERK dependent apoptosis. Moreover, ZALE generated DNA double strand breaks as suggested by the induction γH2AX foci formation. Interestingly, pretreatment of certain cancer cell lines with ZALE, sensitized the cancer cells to cisplatin and other chemotherapeutic drugs. Enhanced caspase activation was observed in the synergistic interaction among chemotherapeutic drugs and ZALE. CONCLUSION: Purification and identification of the bio-active molecules from the ZALE or as a complementary treatment for a sequential treatment of ZALE with chemotherapeutic drugs might be a new challenger to open a new therapeutic window for the novel anti-cancer treatment.