Analysis of Antiangiogenic Potential and Cell Death Mechanism of a Kinetically Inert Platinum Antitumor Agent

Cancer is a multifaceted disease involving various pathological processes, including uncontrolled proliferation, development of resistance, angiogenesis, metastasis, etc. Therefore, chemotherapeutic agents capable of simultaneously inhibiting proliferation, circumventing chemoresistance, and inhibiting angiogenesis can address multiple aspects of cancer progression. We recently identified a highly promising kinetically inert platinum antitumor agent, namely, <b>Pt-1</b>, that can circumvent cisplatin resistance and showed negligible nephrotoxicity. In this study, we explored the antiangiogenic potential and elucidated the detailed mechanism of cell death through which it exerts its antitumor activity. <b>Pt-1</b> strongly inhibited angiogenesis in a zebrafish <i>in vivo</i> model at its therapeutically relevant nontoxic dose. Further, <b>Pt-1</b> exerted antitumor activity through necroptosis- and paraptosis-mediated cell death. Taken together, the combination of antitumor activity with antiangiogenic property in <b>Pt-1</b> makes it a highly promising antitumor candidate.