Mechanistic Insights into the Apoptosis of Cancer Cells Induced by a Kinase‐Responsive Peptide Amphiphile

Organelle targeting is a useful approach in drug development for cancer therapy. Peptide amphiphiles are good candidates for targeting specific organelles because they can be engineered into a wide range of molecular structures, enabling customization for specific functional needs. We have developed a peptide amphiphile, C16-(EY)3, that can respond to tyrosine kinase activity and undergo phosphorylation inside cancer cells. C16-(EY)3 selectively induced apoptosis in cancer cells that overexpressed tyrosine kinase. The self-assembly of peptide amphiphiles on the endoplasmic reticulum (ER) membrane reduced the ER membrane fluidity and triggered ER stress. The mechanism of the cancer cell death induced by C16-(EY)3 was shown to involve phosphorylation by tyrosine kinase, ER stress induction, and the subsequent activation of caspase-4, -12, and -9, which ultimately triggered apoptosis through the activation of caspase-3 and -7. In vivo studies further validated the antitumor efficacy of C16-(EY)3, as transcutaneous administration of the peptide amphiphile inhibited tumor growth in mice. This study elucidated the mechanism of apoptosis induced by the peptide amphiphile, indicating the potential of peptide amphiphiles as organelle-targeting cancer therapeutics and providing a novel strategy for the development of selective and potent anticancer drugs.