Abstract A105: Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through redox modulation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-07, Vol.75 (13_Supplement), p.A105-A105
• Main Authors: Ju, Huaiqiang, Gocho, Takshi, Aguilar, Mitzi, Zhuang, Zhuo-Nan, Fu, Jie, Wu, Min, Yanaga, Katsuhiko, Huang, Peng, Chiao, Paul
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PANCA2014-A105

Pancreatic ductal adenocarcinoma (PDAC) usually develops intrinsic and extrinsic resistances to gemcitabine, and the mechanisms are not well understood. Here we found gemcitabine treatment induced NOX-derived ROS generation through the increase of p22-phox expression via NF-kappaB activation. As ROS levels increased, nuclear translocation of Nrf2 stimulated transcription of cytoprotective antioxidant genes, specially, those encoding enzymes that catalyze glutathione production to reduce elevated ROS as one of intrinsic resistance counter measures. RNAi depletion of Nrf2 enhanced the sensitivity to gemcitabine in multiple PDAC cells. The addition of beta–phenylethyl isothiocyanate (PEITC) inhibited the ROS detoxification process by reducing glutathione levels; this, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our results provide novel pre-clinical knowledge in pancreatic cancer chemoresistance, and combination with a redoxmodulating compound to deplete antioxidants can overcome intrinsic gemcitabine resistance. Our study suggests that a redox-mediated pathway that contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC demonstrates a coordinated and selective cytotoxic effect against pancreatic cancer cells and a new avenue for further clinical studies of this deadly disease. Thus, this combination strategy could prove valuable as a cancer treatment. Note: These results were published in Molecular Cancer Therapeutics as a full-length article before the online publication of this abstract. Citation information: Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation. Huai-Qiang Ju, Takeshi Gocho, Mitzi Aguilar, Min Wu, Zhuo-Nan Zhuang, Jie Fu, Katsuhiko Yanaga, Peng Huang, and Paul J. Chiao. Mol Cancer Ther March 2015 14:788-798. doi:10.1158/1535-7163.MCT-14-0420. Citation Format: Huaiqiang Ju, Takshi Gocho, Mitzi Aguilar, Zhuo-Nan Zhuang, Jie Fu, Min Wu, Katsuhiko Yanaga, Peng Huang, Paul Chiao. Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through redox modulation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer R