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Vitamin A derivatives as antagonists of nicotine effects

Institution: The Burnham Institute for Medical Research
Investigator(s): Xiao-Kun Zhang, Ph.D.
Award Cycle: 2004 (Cycle 13) Grant #: 13RT-0138 Award: $670,085
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Tobacco consumption is a major risk factor of developing lung cancer, the leading cause of death from cancer among both men and women in California. Standard surgery, radiotherapy, and chemotherapy have not resulted in a reduction of morbidity and mortality, or an improvement of quality of life of lung cancer patients. New approaches are therefore urgently needed. This endeavor, however, depends largely on our improved knowledge of the molecular basis of tobacco consumption on lung cancer growth. We recently discovered that nicotine exerts mitogenic effect in lung cancer cells by inducing the expression of TR3 (also called nur77 or NGFI-B), an orphan member of the steroid/thyroid/retinoid receptor superfamily. Paradoxically, TR3 induction is also required for apoptosis of lung cancer cells by migrating from the nucleus to mitochondria, where it interacts with Bcl-2 to initiate apoptosis. These exciting observations offer new approaches to develop novel agents for suppressing the mitogenic effect of nicotine and for inducing apoptosis of lung cancer cells. In searching for such agents, we have observed that the translocation of TR3 from the nucleus to mitochondria requires retinoid X receptor (RXR), a receptor for a class of specific vitamin A derivatives. Moreover, we have identified several new vitamin A derivatives (RXR ligands) capable of inducing RXR nuclear export (referred as rexporters). Based on these results, we hypothesize that rexporters can antagonize the mitogenic effects of nicotine and induce apoptosis of lung cancer cells by inducing TR3 nuclear export and mitochondrial targeting. In this multidisciplinary Research Project application, we propose to study whether rexporters suppress the mitogenic effect of nicotine in lung cancer cells and the underlying molecular mechanisms, with the goals of identifying more effective and specific rexporters for lung cancer therapy. Five aims are proposed to accomplish our goals: (1). To determine the antagonistic effects of rexporters on the mitogenic activity of nicotine in lung cancer cells. (2). To investigate the mechanisms by which rexporters suppress the mitogenic effect of nicotine by inducing TR3 nuclear export. (3). To determine whether rexporters promote lung cancer cell apoptosis by inducing RXR/TR3 mitochondrial localization. (4). To design and synthesize more effective and selective rexporters. (5) To evaluate rexporters in vitro and in vivo. Results from these studies will establish a novel mechanism for suppressing the mitogenic effect of nicotine and inducing tobacco-associated lung cancer cell apoptosis and may generate novel therapeutic agents against lung cancer. Our proposed studies are highly relevant to the goals of TRDRP by addressing important issues regarding molecular controls of the effect of nicotine on lung tumor development and have significant impact on developing more effective agents for tobacco-associated lung cancer prevention and treatment.
Publications

Hypericum sampsonni induces apoptosis and nuclear export of retinoid X receptor-alpha
Periodical: Carcinogenesis Index Medicus:
Authors: Zeng JZ, Sun DF, Wang L, Cao X, Qi JB, Yang T, Hu CQ, Liu W, Zhang XK ART
Yr: 2006 Vol: Nbr: Abs: Pg:

A structure-based approach to retinoid X receptor-alpha inhibition
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Stebbins JL, Jung D, Leone M, Zhang XK, Pellecchia M ART
Yr: 2006 Vol: 281 Nbr: Abs: Pg: 16643-16648

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt
Periodical: Oncogene Index Medicus:
Authors: Han YH, Cao X, Lin B, Lin F, Kolluri SK, Stebbins J, Reed JC, Dawson MI, Zhang XK ART
Yr: 2006 Vol: 25 Nbr: Abs: Pg: 2974-2986

Transcription factors that directly target mitochondria for cell death induction
Periodical: Oncogene Index Medicus:
Authors: Moll UM, Marchenko N, Zhang XK ART
Yr: 2006 Vol: 25 Nbr: Abs: Pg: 4725-43

Exploiting the TR3 interaction with Bcl-2 as a novel therapeutic strategy of cancer and leukemia therapy.
Periodical: Blood Index Medicus:
Authors: Zhai, DY, Sergienko, E, Kitada, S, Luciano, F, Satterswaitk AC, Zhang, XK, and Reed, JC ART
Yr: 2006 Vol: 108 Nbr: 80A-80A Abs: Pg: 256 Part 1

A novel peptide containing a nine amino acid sequence from Nur77 induces Bcl-2-dependent apoptosis in AML.
Periodical: Blood Index Medicus:
Authors: Andreeff, M, Konopleva, M, Watt, JC, Samudio, IJ, Satterthwait, AC, Kitada, S, Zhang, XK, ART
Yr: 0 Vol: 108 (11) Nbr: 736A-736A Abs: Pg: 2607 Part 1

Targeting Nur77 Translocation.
Periodical: Expert Opinion on Therapeutic Targets Index Medicus:
Authors: Zhang, XK ART
Yr: 2007 Vol: 11 Nbr: Abs: Pg: 59-79

An adamantyl-substituted retinoid-derived molec that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nucl recptoor: Effects of modifying its carboxylate grp on apoptosis, proliferation, & pro
Periodical: Journal Medical Chemistry Index Medicus:
Authors: Dawson, MI, Xia, ZB, Liu, G, Fontana, JA,Farhana, L, Patel, BB, Arumugarajah, S, Bhuiyan, ART
Yr: 0 Vol: 50 Nbr: 11 Abs: Pg: 2622-2639

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Bisson,WH, Cheltsov,AV, Bruey-Sedano,N, Lin,B, Chen,J,Goldberger,N, May, LT, Christopoulos ART
Yr: 2007 Vol: 104 Nbr: 29 Abs: Pg: 11927-11932

Nur77 converts phenotype of Bcl-B, an anti-apoptotic protein expressed in plasma cells and myeloma.
Periodical: Blood Index Medicus:
Authors: Luciano,F,Krajewska,M,Ortiz-Rubio,P,Krajewski,S,Zhai,D,Faustin,B,Bruey,JM,Bailly-Maitre,B, ART
Yr: 2007 Vol: 109 Nbr: 9 Abs: Pg: 3849-3855

Nongenomic actions of retinoids:Role of Nur77 and RXR in the regulation of apoptosis and inflammation.
Periodical: Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Index Medicus:
Authors: Zeng, JZ, and Zhang, XK ART
Yr: 2007 Vol: 6 Nbr: Abs: Pg: 315-331

RXR agonists inhibits high glucose induced oxidative stress by repressing PKC activity in human endothelial cells.
Periodical: Free Radical Biology and Medicine Index Medicus:
Authors: Chai, D, Wang, B, hen,L, Pn, J, Zhang, XK and He, B ART
Yr: 2008 Vol: 44 Nbr: Abs: Pg: 1334-1347