Synergistic antitumor effect of ginsenoside Rg3 and cisplatin in cisplatin-resistant bladder tumor cell line

Cisplatin-based chemotherapy is the first-line treatment for metastatic urothelial cell carcinoma. However, for cisplatin-resistant cases, no chemotherapeutic agent has been established as a standard of treatment. This study aimed to investigate the synergistic antitumor effect of ginsenoside Rg3 on cisplatin in cisplatin-resistant bladder cancer cells (T24R2). T24R2 cells were treated with cisplatin and/or ginsenoside Rg3. Cell viability was assessed by the Cell Counting Kit-8 and clonogenic assays. Synergism between ginsenoside Rg3 and cisplatin was determined when the combination index was <1.0. Flow cytometry was used to evaluate the cell cycle distribution. To estimate the changes of proteins associated with the cell cycle and apoptosis following the treatment of ginsenoside Rg3, western blotting and densitometric assays were performed for caspase-3, -8 and -9, cyclin B1, Bcl-2, Bad, p21 and cytochrome c. The Cell Counting Kit-8 and clonogenic assays showed the synergistic antitumor effect of ginsenoside Rg3 on cisplatin, while the combination index was <1.0, confirming the synergism. Cell cycle alterations at the G2/M phase caused by cisplatin were greater after the combination with ginsenoside Rg3. Western blotting and densitometric assay showed that the expression of Bcl-2 was decreased after the combined treatment of ginsenoside Rg3 and cisplatin, whereas the expression of cytochrome c and caspase-3 were increased, suggesting the activation of the intrinsic apoptotic pathway. In conclusion, ginsenoside Rg3 inhibited the proliferation of cisplatin-resistant bladder cancer cells in a synergistic manner with cisplatin. Activation of the intrinsic apoptotic pathway and the enhancement of cell cycle alterations are possible explanations for this result.