Anti-cancer effect of HS-345, a new tropomyosin-related kinase A inhibitor, on human pancreatic cancer

Abstract

Tropomyosin-related kinase A (TrkA) is emerging as an important player in carcinogenic progression. TrkA overexpression, which is associated with cell growth, proliferation, survival, and invasion, has been observed in pancreatic cancer. We therefore synthesized HS-345, a novel TrkA inhibitor, and evaluated its anti-cancer effect and underlying mechanism of action in pancreatic cancer. In this study, HS-345 effectively inhibited the growth and proliferation in three pancreatic cancer cell lines (PANG-1, MIA PaCa-2, and BxPC-3). Activation of the TrkA/Akt signal cascade was also inhibited by HS-345 treatment in a dose-dependent manner. The pro-apoptotic effect of HS-345 was evidenced by increased levels of cleaved caspase-3 and cleaved PARP, and decrease of Bcl/Bax expression via mitochondria membrane potential, as well as elevated numbers of TUNEL-positive apoptotic cells. HS-345 was additionally found to exert anti-angiogenic effect by decreasing the expression of HIF-1 alpha, and VEGF, major factors of angiogenesis, which were also demonstrated by the suppression of tube formation and migration of VEGF-treated human umbilical vein endothelial cells along with inhibition of blood vessel formation by HS-345 in a Matrigel plug assay with mice. Results of our investigation show that HS-345 inhibited the TrkA/Akt signaling pathway resulting in cell growth/angiogenesis inhibition and apoptosis induction. Based on our data, we suggest that HS-345 is a potential candidate for treating pancreatic cancer. Crown Copyright (C) 2013 Published by Elsevier Ireland Ltd. All rights reserved.