Abstract:
Platinum-based drugs, like cisplatin, have been extensively utilized in cancer chemotherapy. However, their clinical application is limited due to the development of off target toxicity and drug resistance. Despite these obstacles, chemotherapy is the most common and effective way of killing cancer cells. Thus, novel platinum(II) and platinum(IV) based complexes with modified ligands have recently been considered as potential candidates to overcome the therapeutic side-effects, bringing the prospect for effective and safe therapy. In this study, we will analyze and establish the chemotherapeutic efficacy and toxicity of the novel platinum(II) complex 5ClSS(II), its platinum(IV) analogue 5ClSS(IV), and two novel platinum(IV) compounds, P-PENT and P-HEX. The research utilizes a comprehensive approach that combines the use of in vitro and in vivo techniques to test the anticancer and safety profile of these complexes on skin and breast cancer. Cytotoxic activity of the complexes has been shown on HaCaT and MDA-MB-231 cell lines with IC50 values in the low micromolar range. The IC50 of P-PENT and P-HEX was found to be approximately ten times lower towards mesenchymal stem cells compared to cancer cells, demonstrating their improved targeting efficiency. All complexes caused apoptosis, release of reactive oxygen species, and simulated key apoptosis and survival pathways such as Bcl-2, Bax, caspase-3, cytochrome c, Akt, and ERK. In vivo chemotherapeutic efficacy and safety of the complexes were also tested on DMBA/TPA-induced skin carcinogenesis model in mice and DMBA-induced breast carcinogenesis model in rats. The two models showed dose-responsive action with respect to inhibition of tumor growth. This anticancer effect was manifested at drug concentrations well below the maximum tolerated dose, and without significant adverse effects. Body and organs weights, and kidney and liver functions were not affected throughout the treatment process, indicating a safe profile. This work highlights the chemotherapeutic potential and safety of these novel complexes which make them candidates for further development towards clinical evaluation. Additional research is needed to understand their mechanism of action and uncover other molecular targets to maximize their clinical use in cancer treatment.
