Tenacissoside G reverses paclitaxel resistance by inhibiting Src/PTN/P-gp signaling axis activation in ovarian cancer cells

Ovarian cancer (OC) is the most common malignant gynecologic tumor, with the highest mortality rate among female reproductive system cancers. Resistance to chemotherapy drugs, which often develops after long-term use, is a major cause of treatment failure. In recent years, traditional Chinese medicine has been widely used in the treatment of tumor for their advantages in improving the efficacy of chemotherapy and alleviating the toxic side effects. Tenacissoside G (Tsd-G), as one of the main active ingredients of Marsdenia tenacissima, exhibits anti-tumor effects. However, its impact on ovarian cancer is not well understood. To assess the role and mechanism of Tsd-G in reversing paclitaxel (PTX) resistance, the reversal fold of Tsd-G in combination with PTX on OC PTX-resistant (A2780/T) cells was determined using CCK-8 assay. The apoptosis level and migration ability of A2780/T cells after 24 h treatment with Tsd-G and PTX were assessed by Hoechst 33,342, flow cytometry, and wound healing assay. Western Blot and Src overexpression plasmid were used to explore the relationship between Src and PTX resistance. The relationship between Src expression and human OC was analyzed by gene expression database. The effect of Tsd-G on P-gp activity was detected by flow cytometry. Western blot and RT-PCR experiments were performed to detect the differences in mRNA and protein expression of Src/PTN/P-gp signaling axis to validate the mechanism of Tsd-G in reversing the resistance to PTX in ovarian cancer. The results showed that Tsd-G reverses PTX resistance in ovarian cancer cells by regulating cell proliferation, cell cycle, inducing apoptosis, and inhibiting migration. The mechanism might associate with the inhibition of Src expression and phosphorylation activation, which in turn inhibits the expression and activity of downstream PTN and P-gp. This study provides a new idea for the treatment of PTX-resistant OC patients and provides theoretical support for revealing the anti-ovarian cancer active ingredients in Marsdenia tenacissima.

Graphical abstract

Tsd-G reverses PTX resistance by inhibiting the Src/PTN/P-gp signaling axis and inducing PTX accumulation in ovarian cancer paclitaxel-resistant cells.