title: 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 (PANC-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-1α 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.
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Ju Hyeon
authors.initials: JH
authors.lastname: Seo
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Jung
authors.forename: Mi Kwon
authors.initials: MK
authors.lastname: Son
authors.forename: Hong Hua
authors.initials: HH
authors.lastname: Yan
authors.forename: Ye-Lim
authors.initials: YL
authors.lastname: Ryu
authors.forename: Jinhee
authors.initials: J
authors.lastname: Kim
authors.forename: Jung Kyun
authors.initials: JK
authors.lastname: Lee
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D020794:Receptor Protein-Tyrosine Kinases
keywords: Angiogenesis; Apoptosis; HS-345; Pancreatic cancer; Tropomyosin-related kinase A (TrkA)