Mitochondrion-Targeted NIR Therapeutic Agent Suppresses Melanoma by Inducing Apoptosis and Cell Cycle Arrest via E2F/Cyclin/CDK Pathway

Abstract

Malignant melanoma is the most fatal form of skin cancer worldwide, and earlier diagnosis and more effective therapies are required to improve prognosis. As a possible solution, near-infrared fluorescent heptamethine cyanine dyes have been shown to be useful for tumor diagnosis and treatment. Here, we synthesized a novel theranostic agent, IR-817, a multifunctional bioactive small-molecule that has near-infrared emission, targets mitochondria in cancer cells, and has selective anti-cancer effects. In in vitro experiments, IR-817 preferentially accumulated in melanoma cells through organic anion transporting polypeptide 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 pathway. Finally, IR-817 significantly suppressed the growth of xenograft tumors in zebrafish and mice. Immunohistochemical staining and hematoxylin and eosin staining revealed that IR-817 induced apoptosis and inhibited tumor cell proliferation without notable side effects. Therefore, mitochondrial-targeting theranostic agent IR-817 may be promising for accurate tumor diagnosis, real-time monitoring, and safe anti-cancer treatments.

Multifunctional Near-Infrared Dye IR-817 Encapsulated in Albumin Nanoparticles for Enhanced Imaging and Photothermal Therapy in Melanoma

“…As shown in Figure 5A, even at a high concentration (80 μM), the cell viability was ~60%, whereas previous studies confirmed that the cell viability of A375 and B16-F10 after 24 h of treatment with 10 μM IR-817 was ~10%. 26 This indicated that BSA@IR-817 could reduce the toxicity of IR-817 significantly. Subsequently, BSA@IR-817 was validated as a photothermal agent for the laser-induced ablation of cancer cells.…”

“…Near-infrared dye IR-817 was synthesized following our previously reported protocol. 26 Antibodies against Ki-67 was purchased from Cell Signaling Technology (CST, Beverly, MA, USA). Antibodies against Cleaved caspase-3 (CC-3) was purchased from Zen-bio (Chengdu, China).…”

“…25 We successfully synthesized IR-817, a new near-infrared fluorescent dye, by coupling IR-808 with dicyclohexylcarbodiimide in our previous study. 26 The in vitro and in vivo imaging studies revealed that IR-817 functioned as an excellent melanoma-targeting agent. In addition, IR-817 entered cells through organic anion-transporting polypeptides (OATPs), displaying structurally inherent tumor targeting.…”

“…Additionally, it was confirmed that IR-817 promoted Bax and inhibited Bcl-2 protein expression, thus initiating a caspase cascade. 26 We believed that this was also one of the reasons why BSA@IR-817, without laser irradiation, could exert some antitumor effects. Consequently, the expressions of CC-3, Bax, Bcl-2, and Ki-67 (the tumor proliferation marker) were detected by immunohistochemistry in the tumors of mice from each group (Figure 7B).…”

A novel mitochondria‐targeting compound exerts therapeutic effects against melanoma by inducing mitochondria‐mediated apoptosis and autophagy in vitro and in vivo

“…Compound 2 (1.42 g, 4 mmol), 9-Anthraldehyde (0.824 g, 4 mmol) and CH 3 COONa (0.328 g, 4 mmol) were dissolved in EtOH (20 mL), and stirred at 70 C for 2 h, then the dark red solution was obtained. 25 Then, the solvent was removed by vacuum evaporation, and CH 2 Cl 2 / CH 3 OH (10/1, v/v) was used as eluent for silica gel column purification to obtain dark red solid products. The IUPAC name: (E)-2-(2-(anthracen-9-yl)vinyl)-1-(5-carboxypentyl)-3,3-dimethyl-3Hindol-1-ium bromide.…”