Anticancer activity of HS-527, a novel inhibitor targeting PI3-kinase in human pancreatic cancer cells

Ye-Lim Ryu; Kyung Hee Jung; Mi Kwon Son; Hong Hua Yan; Soo Jung Kim; Sanghye Shin; Sungwoo Hong; Soon-Sun Hong

doi:10.1016/j.canlet.2014.07.001

Anticancer activity of HS-527, a novel inhibitor targeting PI3-kinase in human pancreatic cancer cells

Cancer Lett. 2014 Oct 10;353(1):68-77. doi: 10.1016/j.canlet.2014.07.001. Epub 2014 Jul 10.

Authors

Ye-Lim Ryu¹, Kyung Hee Jung¹, Mi Kwon Son¹, Hong Hua Yan¹, Soo Jung Kim¹, Sanghye Shin², Sungwoo Hong³, Soon-Sun Hong⁴

Affiliations

¹ Department of Drug Development, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
² Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
³ Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: [email protected].
⁴ Department of Drug Development, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea. Electronic address: [email protected].

PMID: 25016056
DOI: 10.1016/j.canlet.2014.07.001

Abstract

Pancreatic cancer is known to have low 5-year survival rate and poor response to treatment. In this study, we synthesized HS-527, a new PI3-kinase inhibitor, and investigated not only its anticancer activity, but also its mechanism of action in pancreatic cancer cells. HS-527 had higher specificity for PI3K than other kinases and inhibited PI3K/Akt signaling pathway by down-regulating Akt and P70S6K. And HS-527 inhibited the cell growth and proliferation of the pancreatic cancer in a time- and dose-dependent manner, with greater activity than gemcitabine. Even HS-527 showed lower cytotoxicity than gemcitabine in normal cells. When treated with HS-527, the cancer cells appeared apoptotic, increasing the expression of cleaved PARP, cleaved caspase-3, and Bax. Furthermore, HS-527 showed an anti-angiogenic activity by decreasing the expression of HIF-1α and VEGF, and inhibited the migration of endothelial cells, and the formation of new blood vessel in mouse Matrigel plug assay. In this study, we found that HS-527 showed anti-cancer activity through an inhibition of the PI3K/Akt pathway in pancreatic cancer cells, suggesting that HS-527 could be used as a promising therapeutic agent for pancreatic cancer.

Keywords: Angiogenesis; Apoptosis; HS-527; PI3K; Pancreatic cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / pharmacology*
Aminopyridines / toxicity
Angiogenesis Inhibitors / pharmacology*
Angiogenesis Inhibitors / toxicity
Animals
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / enzymology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Mice
Molecular Targeted Therapy
Neovascularization, Physiologic / drug effects
Pancreatic Neoplasms / blood supply
Pancreatic Neoplasms / enzymology*
Pancreatic Neoplasms / pathology
Phosphatidylinositol 3-Kinase / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / toxicity
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / drug effects*
Sulfonamides / pharmacology*
Sulfonamides / toxicity
Time Factors
Vascular Endothelial Growth Factor A / metabolism

Substances

2-amino-N,N-dimethyl-5-(3-(2-methylpyridin-4-yl)-1H-pyrrolo(2,3-b)pyridin-5-yl)pyridine-3-sulfonamide)
Aminopyridines
Angiogenesis Inhibitors
Apoptosis Regulatory Proteins
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Sulfonamides
VEGFA protein, human
Vascular Endothelial Growth Factor A
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt