Aerosolized Bexarotene Inhibits Lung Tumorigenesis without Increasing Plasma Triglyceride and Cholesterol Levels in Mice
Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA. Cancer Prevention Research
(Impact Factor: 4.44).
02/2011; 4(2):270-6. DOI: 10.1158/1940-6207.CAPR-10-0246
Prior studies have shown the retinoid X receptor (RXR) agonist bexarotene has preventive efficacy in rodent models of mammary and lung tumorigenesis albeit causing hypertriglyceridemia and hypercholesterolemia. We reasoned that bexarotene delivered by inhalation may provide sufficient dose directly to the respiratory tract to achieve efficacy while avoiding these side effects. In this study, the chemopreventive activity of aerosolized bexarotene was investigated in the benzo(a)pyrene [B(a)P]-induced mouse lung tumor model as assessed by tumor multiplicity and tumor load. Aerosolized bexarotene significantly decreased tumor multiplicity and tumor load by 43% and 74%, respectively. Our data showed that bexarotene can both inhibit proliferation and promote apoptosis in vivo. Our data also show that aerosolized bexarotene did not increase plasma total cholesterol and triglyceride level compared with diet group. These results indicate that aerosolization may be a safe and effective route of administering bexarotene for chemoprevention of lung cancer.
Available from: Dusica Cvetkovic
- "There has been significant interest in this class of compounds in cancer because an RXR agonist [Targretin (TRG)] is approved clinically for the treatment of cutaneous T-cell lymphoma (Lansigan and Foss 2010) and has demonstrated clinical efficacy in non–small-cell lung cancer (Dragnev et al., 2011; Kim et al., 2011). In addition, this class of compounds has shown efficacy in a variety of mammary and lung cancer models in rodents (Pereira et al., 2006; Wang et al., 2006b, 2009; Liby, et al., 2007; Zhang et al., 2011), and more recently in humans (Dragnev et al., 2011; Kim et al., 2011). However, the elevation of triglycerides levels by 9-cis-RA, TRG, and various retinoids has been known for many years and is a major concern in the use of these agents, particularly in a cancer-prevention setting (Grubbs et al., 2006; Kolesar et al., 2010). "
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ABSTRACT: Examining three RXR agonists [Targretin (TRG), UAB30, and 4-methyl-UAB30 (4-Me-UAB30)], all inhibited mammary cancer in rodents and two (TRG and 4-Me-UAB30) strikingly increased serum triglycerides levels. Agents were administered in diets to female Sprague-Dawley rats. Liver RNA was isolated and microarrayed on the Affymetrix GeneChip Rat Exon 1.0 ST array. Statistical tests identified genes that exhibited differential expression and fell into groups, or modules, with differential expression among agonists. Genes in specific modules were changed by one two or all three agonists. An interactome analysis assessed the effects on genes which heterodimerize with known nuclear receptors. For PPARα/RXR activated genes, the strongest response was TRG > 4-Me-UAB30>UAB30. Many LXR/RXR related genes (e.g., SCD-1 and SREBP-1c which are associated with increased triglycerides) were highly expressed in TRG and 4-Me-UAB30 but not UAB30 treated livers. There was minimal expression changes associated with RAR or VDR heterodimers by any of the agonists. UAB30 unexpectedly and uniquely activated genes associated with the Ah receptor (Cyp1a1, Cyp1a2, Cyp1b1 and NQO1). Based on the Ah receptor activation, UAB30 was tested for its ability to prevent DMBA-induced mammary cancers, presumably by inhibiting DMBA activation, and was highly effective. Gene expression changes were determined by RT-PCR in rat livers treated with Targretin for 2.3, 7 and 21 days. These showed similar gene expression changes at all three time points; arguing some steady state effect. Different patterns of gene expression among the agonists provided insight into molecular differences, and allowed one to predict certain physiologic consequences of agonist treatment.
Molecular pharmacology 01/2013; 83(3). DOI:10.1124/mol.112.082404 · 4.13 Impact Factor
Available from: Laurent Guilleminault
Advances in Cancer Therapy, 11/2011; , ISBN: 978-953-307-703-1
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ABSTRACT: Of the potential sites of cancer development, cancer of the lung accounts for the highest number of cancer deaths each year in the United States (Jemal et al., 2010(1)). Based on its histopathological features, lung cancer is grouped into small cell lung cancer (SCLC; ∼20%) and non-SCLC (NSCLC; ∼80%), which is further divided into three subtypes: squamous cell carcinoma (∼30%), adenocarcinoma (∼50%), and large cell lung carcinoma. Every subtype of lung cancer has a relatively low 5-year survival rate that is attributed, in part, to the fact that they are routinely diagnosed at later histologic stages. Due to this alarming statistic, it is necessary to develop not only new and effective means of treatment but also of prevention. One of the promising approaches is chemoprevention which is the use of synthetic or natural agents to inhibit the initial development of or further progression of early lung lesions (Hong and Sporn, 1997). Many compounds have been identified as potentially effective chemopreventive agents using animal models. Most chemopreventive studies have been performed using mouse models which were developed to study lung adenomas or adenocarcinomas. More recently, models of squamous cell lung cancer and small cell lung cancer have also been developed. This review seeks to highlight mouse models which we helped to develop and presents the results of recent chemopreventive studies that we have performed in models of lung adenocarcinoma, squamous cell carcinoma, and small cell lung cancer.
Progress in molecular biology and translational science 01/2012; 105:211-26. DOI:10.1016/B978-0-12-394596-9.00007-X · 3.49 Impact Factor
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