Platinum(IV) Complexes Suppress Tumor Growth in MDA-MB-231 Cells and a DMBA- Induced Mammary Carcinoma Model.

PURPOSE: The anticancer activity of two platinum(IV) complexes, P-PENT and P-HEX, was evaluated against MDA-MB-231 triple negative breast cancer cells and DMBA-induced mammary carcinoma in rats.

METHOD: MDA-MB-231 and MCF-7 cell viability was evaluated using WST-1 kit. Biological characterization was carried out on MDA-MB-231 cells. Subcellular localization of platinum complexes were assessed with a subcellular fractionation kit and ICP-MS. Apoptosis and ROS production were assessed by flow cytometry and cell-permeant fluorogenic probe 2',7'-dichlorofluorescein diacetate, respectively. Dose escalation study was conducted on rats. Chemotherapeutic activity of P-PENT and P-HEX was evaluated for 4 weeks using a DMBA-induced breast carcinogenesis rat model.

RESULTS

P-PENT and P-HEX were ~ tenfold more cytotoxic than cisplatin against MDA-MB-231 cells and 8.6- and 5.8-fold more cytotoxic against MCF-7 cells, respectively, while showing ~ tenfold lower toxicity to rat bone marrow MSCs (Selectivity Index: 8.9, 9.5 vs. 0.3). Both complexes showed peak intracellular accumulation at 24 h with higher and faster uptake than cisplatin. P-PENT is mostly localized in the nuclear/cytoskeletal fraction (42%) and P-HEX in the cytoplasmic fraction (62%). A significant increase in ROS production and apoptotic type of cell death were observed post treatment with P-PENT and P-HEX. Maximum tolerated doses were 45 and 40 mg/kg for P-PENT and P-HEX, respectively; both significantly inhibited mammary tumor growth (15 mg/kg; IP; weekly) without detectable toxicity.

CONCLUSION

P-PENT and P-HEX exhibited potent antitumor activity against breast cancer both in vitro and in vivo and may be considered as promising candidates for further preclinical investigation.