Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Abstract

Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22 -phox expression via NF-kB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of b-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redoxmediated pathway 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 has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment. Mol Cancer Ther; 14(3); 788-98.Ó2014 AACR.

Keap1–Nrf2 signalling in pancreatic cancer

“…Enhanced sensitivity of AsPC-1 cells treated with cisplatin, phenethyl isothiocyanate and gemcitabine has been observed following Nrf2 knockdown (Ju et al, 2015;Hong et al, 2010;Duong et al, 2014). Similarly, knockdown of Nrf2 in Colo-357 cells resulted in reduced viability after treatment with cisplatin and phenethyl isothiocyanate (Hong et al, 2010).…”

“…ROS comprises oxygen-derived molecules and free radicals which can arise during normal metabolism (Turrens, 2003), and also during cell proliferation or abnormal and stressful events, such as endoplasmic reticulum (ER) stress or oncogenic transformation (Zhang and Kaufman, 2008;Logsdon and Ji, 2013;Kong et al, 2013). Moreover, exogenous toxic environmental agents, such as chemotherapy drugs and cigarette combustion products, may also induce free radicals (Hayes and McMahon, 2009;Ju et al, 2015).…”

“…In Panc-1 cells, Nrf2 suppression enhanced the cytotoxic effects of etoposide (Arlt et al, 2013). Depletion of Nrf2 has been demonstrated to increase MiaPaCa-2 sensitivity to gemcitabine in vitro and in vivo, and limits the ability of these cells to adapt to gemtamicin-induced ROS formation (Ju et al, 2015;Duong et al, 2014).…”

Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

“…Reactive Oxygen Species (ROS) induction is one of the mechanisms for gemcitabine to eradicate cancer cells [23]. Bmi1 was reported to regulate the redox balance and protect cell from the damage of oxidative stress [20].…”

Design, synthesis, and biological evaluation of novel <strong>EF24 </strong>and <strong>EF31 </strong>analogs as potential I&kappa;B kinase &beta; inhibitors for the treatment of pancreatic cancer

“…As the only standard first-line therapy for advanced PC patients, GEM, a conventional cytotoxic drug, exerts favorable anticancer action by breaking down the deoxynucleotide metabolism of PC cells 6,7. However, the increasing occurrence of acquired resistance by PC cells and the nonselective cytotoxicity to normal cells led to the outcomes of GEM monotherapy being extremely poor 8–10. Currently, various combination therapeutic regimens have been assessed in clinical or preclinical practice in the hope of overcoming the intricate mechanism of resistance 11,12.…”