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

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

来源：Cancer Letters, 2014, 353(1): 68-77.

DOI：10.1016/j.canlet.2014.07.001

• PI3K
• HS-527
• Pancreatic cancer
• Apoptosis
• Angiogenesis

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-1 alpha, 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.

• 出版日期2014-10-10