Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis

Mitochondria-targeted
delivery is a promising strategy in anticancer
drug development. Triphenylphosphine cation (TPP+) is the
most widely used mitochondrial-targeting carrier due to the elevated
mitochondrial membrane potential (MMP) in cancer cells. Here, we report
the serendipitous discovery of a mitochondrial-targeting carrier,
compound 23, which exhibited potent anticancer activity
(IC50 = 70 nM, HCC827) with minimal toxicity to normal
cells. Compound 23 selectively accumulates in cancer
cell mitochondria, induces MMP depolarization, and activates mitophagy
via PINK1-Parkin pathway. It also disruptes mitochondrial functions,
elevates ROS levels, and inhibits the xCT-GSH-GPX4 axis, leading to
lipid peroxidation and ferroptotic cell death. In vivo, 23 significantly suppressed the growth of HCC827 xenograft tumors at
10 mg/kg. These findings support compound 23 as a highly
selective and effective mitochondrial-targeting anticancer agent for
further investigation.