Chronic nicotine inhibits the therapeutic effects of gemcitabine on pancreatic cancer in vitro and in mouse xenografts

Abstract

Aim of Study Smoking is an established risk factor for pancreatic cancer and nicotine replacement therapy often accompanies chemotherapy. The current study hs tested the hypothesis that chronic exposure to low dose nicotine reduces the responsiveness of pancreatic cancer to the leading theraputic for this cancer, gemcitabine. Methods The effects of chronic nicotine (1 μm/L) on two pancreatic cancer cell lines in vitro and in a xenogaft model were assessed by immunoassays, Western blots and cell proliferation assays. Results Exposure in vitro to nicotine for 7 days inhibited the gemcitabine-induced reduction in viable cells, gemcitabine-induced apoptosis as indicated by reduced expression of cleaved caspase-3 while inducing the phosphorylation of signaling proteins ERK, AKT and Src. Nicotine (1 μm/L) in the drinking water for 4 weeks significantly reduced the therapeutic response of mouse xenografts to gemcitabine while reducing the induction of cleaved caspase-3 and the inhibition of phosphorylated forms of multiple signaling proteins by gemcitabine in xenograft tissues. Conclusions Our experimental data suggest that continued moderate smoking and nicotine replacement therapy may negatively impact therapeutic outcomes of gemcitabine on pancreatic cancer and that clinical studies in cancer patients are now warranted.

Recombinant expression of different mutant K-ras gene in pancreatic cancer Bxpc-3 cells and its effects on chemotherapy sensitivity

“…This phenomenon may be partly due to the increased phosph-Akt and/or phosph-Erk in mutant clones. As Baneriee et al [19] reported, the reduction in p-Erk contributed to the reduced sensitivity of pancreatic ductal adenocarcinoma (PDAC) to gemcitabine. Over-expressed p-Erk was also reported to enhance the drug resistance to 5-FU [20] and docetaxel [21].…”

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

“…PDAC tumors developed in mice exposed to nicotine display more aggressive features, with increased number of circulating cancer cells and dissemination to the liver, compared with not-exposed mice. Moreover, these tumors are more resistant to gemcitabine chemotherapy (Banerjee, Al-Wadei, & Schuller, 2013). Obesity and abdominal fatness also increase PanIN and PDAC risks (RR: 2) (Aune et al, 2012;Rebours et al, 2015).…”

Evaluation Of Demographic And Clinicopathological Characteristics Of Panreatic Adenocarcinoma Patients

“…Ortanca genel sağ kalım tedavi almayan kol için 1 ay (0,2-1,7) iken almış olan kolda 7 (4,7-9,3) ay idi (p<0,0001). Metastatik hastalar için ortanca PFS 23 hafta (19)(20)(21)(22)(23)(24)(25)(26)(27) idi. Gemsitabin tek başına verildiğinde(n=12) ortanca PFS 9 hafta (0, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]6) iken sisplatin tedaviye eklendiğinde(n=56) 25 (18,9) haftaya uzamıştı (p=0,001).…”