A novel HDAC6 inhibitor exerts an anti-cancer effect by triggering cell cycle arrest and apoptosis in gastric cancer.

Gastric cancer is the second leading cause of cancer-related deaths in the world. SAHA, one of the emerging HDAC inhibitor widely used for cancer treatment, has unignorable side effects, as it is a multi-target HDAC inhibitor. However, it is believed that specifically targeting against fewer HDACs might decrease this cytoxin effect. In our previous work, we have designed and synthesized a series of new compounds, which specifically targets to HDAC6, and TC24 was one of them. In this study, we further demonstrated that TC24 selectively inhibited the activity of HDAC6 other than class I HDACs. TC24 exhibited strong anti-proliferation and anti-motility ability toward gastric cancer cells but had no obvious cytoxin effect on gastric normal GES-1 cells. The anti-cancer effect of TC24 was triggered by G2/M cell cycle arrest, apoptosis and the loss of mitochondrial membrane potential. Bcl-2, cdc 2 and cyclin B1 were decreased while Bax and cleaved-PARP were increased. Also, TC24 suppressed tumor angiogenesis via the reduction of HIF-1α and VEGF. All the above data supported that TC24 was a selective inhibitor of HDAC6 and strongly suppressed the proliferation of gastric cancer cells via inducing cell cycle arrest and cell apoptosis and tumor angiogenesis inhibition, suggesting TC24 is potentially a novel therapeutic agent for gastric cancer and the research on chemical structure of TC24 would promote the understanding of the drug design of related compounds.