title: Synergistic anticancer activity of HS-173, a novel PI3K inhibitor in combination with Sorafenib against pancreatic cancer cells.
abstract: The RAF/MEK/ERK and PI3K/AKT pathways are highly implicated in the development of pancreatic cancer. The principal objective of this study was to assess the synergic effect between Sorafenib (a RAF inhibitor) and HS-173 (a novel PI3K inhibitor) to gain insight into novel therapeutic strategies for treating pancreatic cancer. We first investigated the cytotoxic effect of co-treatment with Sorafenib and HS-173 using the Calcusyn program. Combined treatment of the two drugs synergistically inhibited the viability of Panc-1 cells (combination index<1). Concomitantly, the co-treatment induced G2/M arrest and increased apoptosis with the loss of mitochondrial membrane potential. Apoptosis resulting from the co-treatment was accompanied by increased levels of cleaved caspase-3 and PARP as well as greater numbers of TUNEL-positive apoptotic cells compared to treatment with either drug alone. Furthermore, combined treatment with these drugs decreased the expression of HIF-1α and VEGF which play an important role in angiogenesis. This anti-angiogenic effect was confirmed by the suppressed tube formation of VEGF-induced human umbilical vein endothelial cells and inhibition of blood vessel formation in a Matrigel plug assay in mice. Taken together, our study demonstrates that combined treatment with Sorafenib and HS-173 has a synergistic anti-cancer effect on pancreatic cancer cells, indicating that simultaneously targeting the RAF/MEK and PI3K/AKT pathways can induce a synergistic inhibitory effect on pancreatic cancers in which both pathways are activated. Based on the observations from our study, we suggest that the combined administration of these two drugs may be considered to be a new therapeutic regimen for treating pancreatic cancer.
authors: College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Sun-Mi
authors: SM
authors: Yun
authors: Kyung Hee
authors: KH
authors: Jung
authors: Hyunseung
authors: H
authors: Lee
authors: Mi Kwon
authors: MK
authors: Son
authors: Ju-Hyeon
authors: JH
authors: Seo
authors: Hong Hua
authors: HH
authors: Yan
authors: Byung Hee
authors: BH
authors: Park
authors: Sungwoo
authors: S
authors: Hong
authors: Soon-Sun
authors: SS
authors: Hong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; C577242:ethyl 6-(5-(phenylsulfonamido)pyridin-3-yl)imidazo(1,2-a)pyridine-3-carboxylate; D009536:Niacinamide; D000077157:Sorafenib