Anti-tumor effect of mitochondrial targeted small molecule IR-780 on cisplatin-resistant bladder cancer cells

Abstract

Objective To study the anti-tumor effect of IR-780, a mitochondrial targeting small molecule, on cisplatin-resistant T24 cell line (T24/DPP). Methods T24/DPP cell line was constructed by repeated and discontinuous stimulation of T24 cells with cisplatin. After the drug-resistant cells were treated with different concentrations of IR-780, cell viability was detected by CCK-8 assay and cell migration was measured by wound healing assay. The suborganelle localization of IR-780 was determined by confocal fluorescence microscopy with aid of mitotracker treatment. Cell apoptosis and production of mitochondrial reactive oxygen species (ROS) were determined by flow cytometry. T24/DPP cells were injected subcutaneously into 6-~8-week-old male nude mice to establish a tumor-bearing nude mouse model. The tumor-bearing mice were randomly divided into 3 groups, including control group (5 mg/kg PBS), DOX group (5 mg/kg DOX) and IR-780 group (5 mg/kg IR-780). After intraperitoneal administration of IR-780, the accumulation of IR-780 were detected by near-infrared in vivo imaging system and confocal fluorescence microscopy, while the tumor volume and weight were measured. Results ① In vitro, IR-780 inhibited the proliferation and migration of T24/DPP cells in a dose-dependent manner (P < 0.05). IR-780 was selectively accumulated in the mitochondria of T24/DPP cells. With the increase of IR-780 concentration, the production of mitochondrial ROS and the rate of apoptosis in T24/DDP cells were increased (P < 0.05). ② In vivo, near-infrared imaging and frozen sections of tumor tissue showed that IR-780 preferentially accumulated in the tumor of tumor-bearing nude mouse model. The tumor volume and weight of the IR-780 group were significantly less and lower when compared with the control group (P < 0.05) and DOX group (P < 0.05). Conclusion IR-780 can significantly inhibit the growth of T24/DDP cells and subcutaneous tumor xenografts in nude mice, and the mitochondrial pathway might be involved in the apoptosis of T24/DPP cells induced by IR-780.

Keywords

• bladder cancer
• tumor targeting
• ir-780