Study on the Anticancer Effects of the Indazole C7 Derivative in Hypopharyngeal Cancer Cells

Abstract

Indoleamine 2,3-dioxygenase (IDO1) is a heme-containing enzyme mainly responsible for the metabolism of tryptophan to kynurenine. Due to its immunosuppressive function, the inhibitors of IDO1 have been intensively developed for the re-activation of anti-cancer immune response. Based on the well-known structure of IDO1 active site and a crucial role of indazole moiety for IDO1 inhibition activity, we synthesized a novel group of designed indazole-containing IDO1 inhibitors. In vitro experiments demonstrated that among this group of derivatives, compound C7 possesses potential inhibitory effects on cancer cell growth. In the present study, we elucidated the anticancer mechanisms of compound C7 on hypopharyngeal cancer. The results showed that C7 expressed cytotoxic effects on hypopharyngeal cancer cells FaDu while human dental pulp stem cells HDPSC and breast cancer cells MCF7 were tolerant to C7 treatment. At the molecular
level, C7 inhibited FaDu cell proliferation by suppressing the expression of Cyclins and Cyclin-dependent kinases (cdk), which are key regulators of cell cycle progression. At higher concentrations, C7 induced irreversible DNA damage, leading to the activation of programmed cell death. In addition, C7 significantly inhibited migration, and invasion of FaDu cells. Collectively, these findings indicate that compound C7 is a promising IDO1 inhibitor and exhibits potent antitumor activity on hypopharyngeal cancer