Abstract 5554: PBI-05204, a supercritical CO2extract ofNerium oleander, inhibits the growth of human pancreatic cancer in a Panc-1 orthotopic model by down-regulation of PI3k/mTOR pathways.

Recent studies have suggested that cardiac glycosides (CGs), such as oleandrin, have an ability to inhibit the proliferation of various cancer cells, including those from pancreatic, non-small cell lung cancer, prostate, colon and breast cancers. However, the inhibitory effect of oleandrin or extracts containing this CG on the growth of human pancreatic cancer xenografts has not been assessed. In this study, the anticancer activity and related pharmacology of the botanical drug PBI-05204, a supercritical CO2 extract of Nerium oleander, was examined in a human pancreatic Panc-1 orthotopic mouse model. Five out of 7 (70%) of control mice exhibited tumor growth measurable by imaging. In contrast, only one out of seven mice treated for 6 weeks with PBI-05204 (40 mg/kg) exhibited a measureable orthotropic tumor. At 20 mg/kg, the average tumor weight (51 ± 58 mg) in mice treated with PBI-05204 was markedly reduced from that in control (134 ± 99 mg). In contrast, gemcitabine (80 mg/kg) did not appear to inhibit the proliferation of this particular tumor. Histopathological examination of serial sections from each pancreas showed that the pancreas of 3/6 mice treated with PBI-05204 (40 mg/kg) were normal while the other 3/6 had tumor sizes less than 4 mm3 (control range: 55 to 500 mm3). Ki-67 staining was substantially reduced in pancreatic tumors treated with PBI-05204 (20 mg/kg) compared to that of control, suggesting that PBI-05204 indeed inhibited the proliferation of Panc-1 tumor cells. Mechanistically, tissue proteomic array analyses suggest that PBI-05204 suppresses the expression of phosphorylation of Src, Akt, S6, 4EPB1, and VEGF in a conc.-dependent manner. The effects of PBI-05204 on suppression of these proteins were further confirmed by immunohistochemical staining of pancreatic tumor tissues and Western blotting of tissue lysates. To delineate whether PBI-05204 also regulated these important oncogenic pathways in Panc-1 cells in vitro, Panc-1 cells were treated with PBI-05204 (0.3 to 1.2 μg/ml) for 24 hrs and subjected to examination of signaling protein expression. The cellular expression of these important signaling proteins was also markedly reduced by PBI-05204 in a conc.-dependent manner while proliferation of Panc-1 cells was notably reduced. Taken together, these results suggest that PBI-05204 exerts potent anticancer activity in this human pancreatic cancer Panc-1 orthotropic mouse model that may, in turn, be mediated by down-regulation of PI3k/Akt and mTOR pathways. Given the observed PBI-05204 mediated reduction in tumor growth of human Panc-1 tumor cells, we are currently determining whether pancreatic tumor cells are able to continue growing when drug treatment is discontinued. The results will be presented at the annual meeting. This study was supported in part by Phoenix Biotechnology, Inc. Citation Format: Yong Pan, Sun-Jin Kim, Patrea Rhea, Carrie Cartwright, Ho Jeong Lee, Crandell Addington, Mihai Gagea, Robert A. Newman, Peiying Yang. PBI-05204, a supercritical CO2 extract of Nerium oleander, inhibits the growth of human pancreatic cancer in a Panc-1 orthotopic model by down-regulation of PI3k/mTOR pathways. [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 5554. doi:10.1158/1538-7445.AM2013-5554