Pharmaceutical research · 2026
Platinum(IV) Complexes Suppress Tumor Growth in MDA-MB-231 Cells and a DMBA- Induced Mammary Carcinoma Model.
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Slika Amjad, Al Alam Saba, Chacra Joelle Bou, Haydar Christina, Jaoude Chris Abou, Gharios Joe Bou, Mrad Joya Maria, Mehanna Stephanie, Elias Maria George, Deo Krishant M, Taleb Robin I, Aldrich-Wright Janice R, Daher Costantine F
Аннотация
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.
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.