Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells

The development and optimization of metal-based anticancer
drugs
with novel cytotoxic mechanisms have emerged as key strategies to
overcome chemotherapeutic resistance and side effects. Agents that
simultaneously induce ferroptosis and autophagic death have received
extensive attention as potential modalities for cancer therapy. However,
only a limited set of drugs or treatment modalities can synergistically
induce ferroptosis and autophagic tumor cell death. In this work,
we designed and synthesized four new cycloplatinated (II) complexes
harboring an isoquinoline alkaloid C∧N ligand. On
screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased
resistance factors, and improved anticancer activity compared to cisplatin.
Furthermore, Pt-3, which we demonstrate can initiate
potent ferritinophagy-dependent ferroptosis, exhibits less toxic and
better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug
development in cancer treatment.