Nicotinic modulation of therapeutic response in vitro and in vivo

Abstract

Tobacco use significantly increases the risk of developing cancer. Moreover, there is growing evidence that tobacco use decreases survival in cancer patients. Nicotine, a systemically available component of tobacco, is associated with tumor promotion and decreased apoptosis in cell culture; however, the role of nicotine on response to radiotherapy (RT) or chemoradiotherapy (CRT) in vivo has not been evaluated. Our study evaluated the effects of nicotine administration on cancer cell survival in cell culture and mouse models. Nicotine increased survival in two cell lines following RT in vitro. Nicotine administration in mice during fractionated RT or CRT increased xenograft regrowth as compared to RT or CRT alone. Nicotine increased hypoxia-inducible factor 1-alpha (HIF-1a) expression in tumor xenografts without altering expression of carbonicanhydrase, a clinical marker of tumor hypoxia. The effects of nicotine on HIF-1a expression were transient, returning to baseline levels within 2-3 days after nicotine removal. Further mechanistic studies indicated that inhibition of phosphoinositide-3-kinase (PI3K) prevented nicotine-mediated increases in HIF-1a expression as well as the prosurvival effects of nicotine on RT. These findings imply that during tobacco use, nicotine may function as a systemic agent through acute and reversible regulation of HIF-1a expression and a decreased therapeutic response.Tobacco use is the most significant preventable risk factor for the development of lung cancer and continued tobacco use during cancer treatment is associated with poor therapeutic outcomes. 1-3 Analysis of the effects of tobacco use in cancer patients demonstrates that smoking decreases survival in both tobacco-related and nontobacco-related cancers. 4 Importantly, the effects of tobacco use appear to be systemic rather than localized and thus supporting the role of a systemically available agent as a mediator of the adverse effects of tobacco.Nicotine is a systemically available agent of tobacco that is currently advocated as a clinical standard of care for smoking cessation. 5 As one of more than 7,000 compounds in tobacco smoke, nicotine has the capacity to penetrate all tissues in the body and bind to a spectrum of nicotinic acetylcholine receptors (nAChR) present on both normal (noncancerous) and cancerous tissue. Nicotinic activation of nAChRs in cancerous tissue leads to broad downstream activation of several tumor promoting proteins including activation of the phosphoinositide kinase-3 (PI3K)-Akt cascade as well as the Ras-Raf-MEK-ERK1/2 cascade, resulting in increased proliferation, angiogenesis, invasion, metastasis and decreased apoptosis. [6][7][8] In parallel, nicotine administration has been shown to decrease the cytotoxic effects of chemotherapy and radiotherapy (RT) in vitro 9-12 ; however, no studies have evaluated the effects of nicotine on therapeutic response in vivo.Separate studies demonstrate that nicotine administration significantly increases hypoxia inducible factor-1 alpha (HIF1a) in vitro. 1...

Differential effects of patient-related factors on the outcome of radiation therapy for rectal cancer

“…Accordingly, over-expression of HIF-1α and other hypoxia-responsive genes has been associated with increased risk of treatment failure and recurrence and reduced overall and disease-free survival [40–44]. Not only does smoking cause a low-grade hypoxia due to elevated carbon monoxide levels [18], but also nicotine induces HIF-1α expression leading to radioresistance in a lung cancer xenograft model [19]. …”

“…Short term starvation and ketogenic diets, which lead to lower availability of glycolysis substrate, have been demonstrated to enhance the effect of radiation treatment in mouse glioma models [16,17]. Smoking may cause a low-grade chronic hypoxic condition due to elevated carbon monoxide levels and pharmacological actions of nicotine [18,19]. Some over the counter medications such as Aspirin and Ibuprofen are known to act on these pathways [20,14].…”

Organ preservation with targeted rapamycin nanoparticles: a pre-treatment strategy preventing chronic rejection in vivo

“…In these experiments, UW solution was augmented with TRaM, empty micelles, free rapamycin, or DMSO vehicle. Following 6, 12, 18, 24, or 72 hours of reperfusion, MCEC protein lysates were collected and analyzed by western blot as previously described 14. Briefly, cells were washed, detached mechanically, pelleted and lysed with M-PER Mammalian Protein Extraction Reagent (Thermo Fisher Scientific, MA) that contained 1× phosphatase and 1× protease cocktail inhibitors (Thermo Fisher Scientific, MA).…”

A retrospective evaluation of associations between chronic obstructive pulmonary disease, smoking, and efficacy of chemotherapy and selected laboratory parameters in patients with advanced non-small cell lung cancer

“…In addition, in vitro and in vivo studies indicate that cigarette smoking worsens the response of cancer to chemotherapy [9]. …”