Abstract 3083: Novel inhibitor GZ17-06.12 suppresses pancreatic cancer tumorigenesis

Abstract

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) or pancreatic cancer is one of the most lethal malignancies in humans. The survival rate for two years is very limited in most of cases (10%) after diagnosis of this disease. This is because current therapeutic regimens have limited effectiveness. Novel therapeutic targets are needed to treat this disease. GZ17-06.12 contains a nutraceutical for its anti-cancer properties, in several cancers. Crude extracts of the plant Arum palaestinum Boiss used in traditional Israeli and Palestinian medicine, have demonstrated cytostatic and cytotoxic activities in colon, prostrate and lung carcinoma. Therefore, we hypothesize that GZ17-06.12 will inhibit tumor progression and metastasis in PDAC. Experimental Procedure: In this study, we have determined cell proliferation, pancosphere formation and apoptosis following treatment of different doses oGZ17-06.12 for 24-72 hours using MiaPaCa-2 and S2-007 human pancreatic cancer cells. Cell cycle distribution and apoptosis were measured using flow cytometic analysis. Orthotopic pancreatic cancer model in athymic mice was developed and GZ17-06.12 was given orally for 20 days to those mice. Proliferative markers, pEGFR/pAkt and apoptotic markers, Bax/Bcl-2, were monitored following treatment with GZ17-06.12 in both in vivo and in vitro models. Metastatic markers, MMP-2 and MMP-9 were measured in metastatic tissues in orthotopic models. Results: GZ17-06.12 inhibited proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. Cell cycle analysis suggested that cells were arrested in S and G2 phase following treatment. In addition, GZ17-06.12 induced apoptosis in both in vitro and in vivo pancreatic cancer. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, GZ17-06.12 decreased the number and size of the pancospheres in S2-007 cells with concomitant inhibition of pancreatic cancer stem cell markers, DCLK1, Lgr5 and EpCam. The effect of GZ17-06.12 suppressed tumor growth and metastatic potential as indicative of MMP-2 and MMP-9 activity in primary and metastatic tumors. Conclusions: GZ17-06.12 significantly reduces tumorigenesis and metastasis in both in vitro and in vivo pancreatic cancer models, inhibiting proliferation with concomitant increase of apoptosis. Citation Format: Santanu Paul, Lisa Stehno-Bittel, Animesh Dhar. Novel inhibitor GZ17-06.12 suppresses pancreatic cancer tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3083.