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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Gamma-Amino Butyric Acid Inhibits the Nicotine-Imposed Stimulatory Challenge in Xenograft Models of Non-Small Cell Lung Carcinoma

Author(s): H. A.N. Al-Wadei, M. H. Al-Wadei, M. F. Ullah and H. M. Schuller

Volume 12 , Issue 2 , 2012

Page: [97 - 106] Pages: 10

DOI: 10.2174/156800912799095171

Price: $65


Non-small cell lung carcinoma (NSCLC) is the leading type of lung cancer; smoking is a documented risk factor. Nicotinic acetylcholine receptor (nAChR)-mediated intracellular signaling in response to nicotine has recently been implicated in the growth regulation of NSCLC. In the current study nude mice carrying xenografts of the human lung NSCLC cell lines NCI-H322 or NCI-H441 were used as animal models. Nicotine administration and gamma aminobutyric acid (GABA) treatment lasted for 30 days. Catecholamines, cortisol, GABA, and cAMP were analyzed in blood and tumor tissues by immunoassays. Expression of nicotinic receptors and effector proteins in the xenografts was assessed by Western blotting. Our data indicate that nicotine stimulated the growth of NSCLC xenografts via modulation of nAChR upregulation and activation of cAMP signaling. The nicotine-treated group showed an enhanced level of stress neurotransmitters and second messenger cAMP in serum, blood cellular fraction, and xenograft tissues. Activation of critical proteins in the oncogenic pathway, including CREB, ERK, Akt, and Src, and upregulation of α-4 and α-7 subunits of nAChR provided mechanistic insight for the observed stimulatory effect of nicotine. Interestingly, GABA, being an antagonist to cAMP signaling, showed a promising intervention by reversing the stimulatory effect of nicotine on cancer growth and all signaling pathways. GABA has potential to lower the risk of NSCLC among smokers and could be used to enhance the clinical outcome of standard cancer intervention strategies.

Keywords: GABA, intervention study, NSCLC, nAChR drug target, nicotine, smoking, xenografts, adenocarcinoma, cyclic adenosine monophosphate, nicotinic acetylcholine receptor, glutamic acid decarboxylase, bicinchoninic acid

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