Enhanced inhibition of proliferation of pancreatic cancer cells by combination of Gemcitabine and Phellodendron amurense bark extract: target identification

Jingjing Gong, James W Freeman and Addanki P Kumar

Department of Urology, School of Medicine, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX-78229

Pancreatic cancer (PanCA) is a leading cause of cancer-related death in the world due to rapid disease progression and high invasiveness. In addition, development of therapeutic resistance to chemotherapeutic agents is one of the challenges for developing effective strategies for PanCA. Phellodendron amurense is a widely used Chinese herbal medicine that has been used as antidiarrheal, astringent anti-inflammatory agent. Recent studies from our laboratory demonstrated that this extract inhibits prostate cancer cell proliferation through modulation of multiple targets including Akt, transcription factors cyclic-AMP response element binding protein (CREB) and NFκB and their downstream targets such as Cyclin D1 and Cox-2. Given the published data showing activation of these signaling molecules during PanCA development, we explored the utility of Nexrutine (Nx, Phellodendron amurense bark extract) alone and in combination with Gemcitabine (standard of care for PanCA) in PanCA to examine if it can either enhance the effects of Gemcitabine or overcome chemoresistance. Human pancreatic cancer cells that differ in the status of K-Ras (BxPC-3 with wild type K-Ras and CaPan-2, MIA PaCa-2, AsPC-1 with mutant K-Ras) and non tumorigenic HPNE-Ras cells were tested for growth inhibition, apoptosis, necrosis, Cox-2 expression and activity following treatment with Nx. Our data indicate that Nx can significantly inhibit proliferation of these five cell lines with IC50 varying from 50-100 µg/ml depending on the cell type. Results also indicate that Nx inhibits proliferation of PanCA cells through induction of apoptosis and necrosis. Further we have identified that anti-proliferation effects of Nx is associated with reduction in the level (Cox-2) and activity (PGE2 and PGF) in multiple PanCA cell lines. Interestingly PGE2 receptor EP2 is also modulated in response to Nx treatment suggesting an important role for PGE2-mediated signaling in Nx-induced inhibition of pancreatic cancer cell growth. In addition, in vitro, Nx increased the inhibitory effect of Gemcitabine on cell proliferation in MIA PaCa-2 and CaPan-2 but not in AsPC-1 pancreatic cancer cells. These results indicate that molecular targeting of multiple signaling pathways in combination with Gemcitabine may improve the sensitivity probably by increased apoptosis and inhibition of invasion along with down regulation of PGE2/Cox-2 signaling (Supported by pilot funds from Cancer Therapy and Research Center, San Antonio, TX).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5389.