Suberoylanilide Hydroxamic Acid Suppresses Highly Aggressive Human Pancreatic Cancer PaTu8988Cells Dominant Vasculogenic Mimicry And Its Mechanisms

Pancreatic cancer is one of the most aggressive human malignancies with aextremely low5-year survival rate. Hence, the search for more effective anti-pancreaticcancer agents is urgent. In this study, we found that histone deacetylase inhibitor(HDACi), suberoylanilide hydroxamic acid (SAHA), inhibited the proliferation andcell-dominant vasculogenic mimicry (VM) of metastatic pancreatic cancer PaTu8988cells. Our results showed tha SAHA dose-dependently inhibited PaTu8988pancreaticcancer cell growth with the IC-50of (3.4±0.7) μM, and has little cytotoxicity on humannormal peripheral blood cells. Mechanistic studies revealed that SAHA suppressedPaTu8988cell cycle progression through inducing G2/M arrest, which was associatedwith cyclin-dependent kinase1(CDK-1)/cyclin-B1degradation and p21/p27upregulation. At high dosage, SAHA induced PaTu8988cell apoptisis accompanied withthe degration of PARP and Caspase3. Additionally, SAHA suppressed PaTu8988cell invitro migration and cell-dominant tube formation or VM, which was accompanied bysemaphorin-4D (Sema4D) and integrinβ5down-regulation. Taken together, SAHAinhibitd the proliferation of PaTu8988cells and induced cell cycle arrest at G2/M phasewhile induced cell apoptosis at high dosage; furthermore, SAHA suppressed Sema4Dand integrinβ5expression to inhibit tumor cell-dominant vasculogenic mimicry, and haslittle or no cytotoxicity at any of the dosages tested. These results warrant furtherinvestigation of SAHA as a candidated anti-pancreatic cancer and anti-cancer drug.