Abstract 2063: Synergistic anticancer activity of Sorafenib in combination with HS-173, a novel PI3K inhibitor against pancreatic cancer cells
| Autor: | Byung Hee Park, Kyung Hee Jung, Soon-Sun Hong, Hyunseung Lee, Sun-Mi Yun, Hong Hua Yan |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Cancer Research. 73:2063-2063 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | The K-RAS mutation, resulting in activation of the Raf/MEK/ERK pathway, has been implicated in pancreatic cancer development. And the PI3K/Akt pathway is highly activated in pancreatic cancer and considered to be a cancer hallmark. The principal objective of this study was to assess the synergic effect between Sorafenib (a Raf inhibitor) and HS-173 (a novel PI3K inhibitor) along with the underlying mechanism 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 with the two drugs synergistically inhibited the viability of Panc-1 cells (combination index < 1). Concomitantly, co-treatment with Sorafenib and HS-173 induced G2/M arrest and increased apoptosis with the loss of mitochondria potential. Apoptosis resulting from co-treatment with Sorafenib and HS-173 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 HIF-1α and VEGF, two factors that play an important role in angiogenesis. The anti-angiogenic effect of simultaneous treatment with Sorafenib and HS-173 was confirmed by observing 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 demonstrated that combined treatment with Sorafenib and HS-173 has a synergistic anticancer 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. Citation Format: Sun-Mi Yun, Kyung Hee Jung, Hyunseung Lee, Byung Hee Park, Hong Hua Yan, Soon-Sun Hong. Synergistic anticancer activity of Sorafenib in combination with HS-173, a novel PI3K inhibitor against pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2063. doi:10.1158/1538-7445.AM2013-2063 |
| Databáze: | OpenAIRE |
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