Mitochondrion-targeted NIR therapeutic agent suppresses melanoma by inducing apoptosis and cell cycle arrest via E2f/Cyclin/CDK pathway. Mus musculus

Malignant melanoma is the most mortally form of skin cancer in the world. Early diagnosis and effective therapy of melanoma remains a challenge. Near-infrared fluorescent (NIR) heptamethine cyanine dyes have been shown to possess abilities for tumor diagnosis and treatment. Here, we synthesized a novel theranostic agent IR-817, a multifunctional bioactive small-molecule, simultaneously exhibiting near-infrared imaging, cancer-cell mitochondrion-targeted and anti-cancer activities. In vitro experiments, IR-817 not only preferentially accumulated in melanoma cells through organic-anion-transporting polypeptide (OATP) transporters, but also selectively inhibited the growth of tumor cells by inducing mitochondrial-dependent intrinsic apoptosis. Mechanistically, IR-817 caused G0/G1 cell cycle arrest by targeting the E2f/Cyclin/CDK/CKI pathway. Finally, IR-817 significantly suppressed tumor growth of xenograft tumor in zebrafish and mice. Immunohistochemical and H&E staining revealed that IR-817 induced apoptosis and inhibited tumor cell proliferation without notable side effects. Therefore, the mitochondrial targeting theranostic agent may be promising for tumor precise diagnosis, real-time monitoring and anti-cancer activities with high safety.