Novel platinum(IV) complexes as potential chemotherapeutic and radiosensitizing agents in HR+ breast cancer treatment.

PURPOSE Effectiveness of platinum-based chemotherapy is often hindered by resistance and systemic toxicity. Novel platinum(IV) complexes, functionalized with O,O'-dialkylated (S,S)-ethylenediamine-N,N'-di-carboxylate ligands, were synthesized to improve cytotoxicity, selectivity, and radiosensitizing potential. Their anticancer properties were evaluated in vitro on two cancer cell lines with different sensitivities to cis-Pt, MCF-7, and HTB 140, as well as on non-transformed fibroblasts (MRC-5).

MATERIALS AND METHODS The cytotoxic effects of butyl-Pt, pentyl-Pt, and cis-Pt were assessed using the MTT assay. The antiproliferative effect was evaluated using BrdU incorporation, while apoptosis was confirmed by DNA fragmentation, Annexin-V/7-AAD staining, and Western blot analysis of Bax and Bcl-2 expression. Cell cycle analysis was performed via flow cytometry. SRB and clonogenic assays were used to evaluate radiosensitization after γ-irradiation.

RESULTS Butyl-Pt and pentyl-Pt exhibited dose- and time-dependent cytotoxicity, with greater potency than cis-Pt and strong selectivity for MCF-7 cells. They significantly suppressed proliferation, induced S-phase arrest, and triggered apoptosis via a shift in the Bax/Bcl-2 ratio. When combined with γ-irradiation (1-4 Gy), both complexes demonstrated enhanced potency in inhibiting growth and reducing clonogenic survival, with butyl-Pt showing the strongest radiosensitizing effect.

CONCLUSIONS These findings suggest that butyl- and pentyl-functionalized platinum(IV) compounds hold promise as potential chemotherapeutic and radiosensitizing agents in HR+ breast cancer treatment.