Tripterygium glycosides sensitizes cisplatin chemotherapeutic potency by modulating gut microbiota in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy with limited therapeutic options. Previous research has demonstrated that Tripterygium glycosides (GTW) can enhance effectiveness of cisplatin (DDP) chemotherapy against EOC. However, the underlying mechanism of GTW alleviating EOC still remains unclear. In this article, an ID8 cell-derived xenograft mouse model was established to evaluate the anti-tumor efficacy of GTW combined with DDP. Consistent with previous findings, the results suggested that GTW combined with DDP can exhibit a stronger tumor suppressive effect than DDP alone. Additionally, GTW was found can further exert gastrointestinal protection against DDP by reducing pathological damage on colon tissue. Secondly, to verify whether gut microbiota play an instrumental role in GTW's anticancer effect, we treated mice models with antibiotic to eliminate gut microbiota. And our experimental results indicated that all drug groups showed a weaker tumor suppressive effect and more severe gastrointestinal damage post antibiotic supplement. At genus level, the relative abundance of Lactobacillus was dramatically diminished by the antibiotic treatment, while combined treatment of GTW and DDP can significantly restore the level. Moreover, we performed Lactobacillus acidophilus transplantation and healthy mice fecal microbiota transplantation experiments to further investigate the link between the anticancer effect of GTW and gut microbiota. Our results suggested that both cisplatin-sensitizing and intestinal barrier-protecting effects of GTW can be recovered to a different extent. In conclusion, our results indicated that GTW is a promising chemosensitization and intestinal barrier repair drug for EOC, and the potential mechanism may corelate with the restoration of the compromised intestinal microbial balance.

Tripterygium glycosides reverse chemotherapy resistance in ovarian cancer by targeting the NRF2/GPX4 signal axis to induce ferroptosis of drug-resistant human epithelial ovarian cancer cells.

Cisplatin resistance is the main cause of postoperative recurrence and difficulty in the treatment of ovarian cancer. It is urgently needed to identify therapeutic drugs with unique functions to overcome the current challenges in the treatment of ovarian cancer. In this study, we found that TG promoted the accumulation of ROS and MDA in A2780/DDP cells and downregulated the expression of key antioxidant molecules. In vivo, the survival rate of tumor-bearing nude mice was prolonged by TG without significant hepatotoxic reaction. The expression of key antioxidant molecules in tumor tissues was consistent with that in vitro. These findings revealed that TG disrupted homeostasis of redox reactions and induced ferroptosis in A2780/DDP cells, thereby enhancing cisplatin chemosensitivity of ovarian cancer. Overall, TG may be a novel potential therapeutic option for reversing resistance to cisplatin chemotherapy.

Synergistic effect of Tripterygium glycosides and cisplatin on drug-resistant human epithelial ovarian cancer via ILK/GSK3ß/Slug signal pathway.

The side-effects of therapeutic drugs and the intrinsic or acquired cisplation resistance are considered impediments in the clinic treatment of human epithelial ovarian cancer, which contribute heavily to the startlingly high mortality. It is imperative to look for drugs to inhibit cancer and minimize the chemotherapy resistance safely and effectively from the Chinese herbal medicine. In the present study, we evaluated the anti-cancer effect of Tripterygium glycosides (GTW) and its sensitizing effect with cisplation (DDP) both in vitro and in vivo. The 5-ethynyl-2'-deoxyuridine (EdU) proliferation assay, transwell assay, and scratch wound healing assay demonstrated that GTW and DDP+GTW prominently inhibited the proliferation, migration, and invasion of SKOV3/DDP cells. In addition, treatment using GTW and DDP+GTW for 24 h significantly decreased the expression of ILK, p-AKT, p-GSK3ß, N-Cadherin, and Slug, and markedly enhanced the expression of E-cadherin. Moreover, animal results confirmed that GTW and DDP+GTW significantly inhibited the tumor volume, increased the apoptosis of tumors cells and reduced the production of tumor markers CA125 and HE4 in mice serum. Similar to the results in vitro, GTW and DDP+GTW significantly inhibited the expression of proteins in epithelial-mesenchymal transition (EMT) and ILK/GSK3ß/Slug signal pathway in tumors in vivo. In conclusion, our results indicated that GTW may be served as a potential therapeutic drug combination with DDP to treat drug resistant ovarian cancer via regulating ILK/GSK3ß/Slug signal pathway.