Mehta R G, Williamson E, Patel M K, Koeffler H P
Department of Surgical Oncology, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
J Natl Cancer Inst. 2000 Mar 1;92(5):418-23. doi: 10.1093/jnci/92.5.418.
Chemoprevention of breast cancer is an active area of investigation. Recent in vivo and in vitro studies have shown that thiazolidinediones (e.g., troglitazone) and retinoids are able to inhibit the growth of breast cancer cells. Troglitazone mediates its action via peroxisome proliferator-activated receptor gamma (PPARgamma). We evaluated the ability of troglitazone, alone or in combination with retinoids, to prevent the induction of preneoplastic lesions by 7,12-dimethylbenz[a]anthracene (DMBA) in a mouse mammary gland organ culture model.
Mammary glands of BALB/c mice were treated with DMBA (2 microg/mL) to induce preneoplastic lesions in organ culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for retinoic acid receptor [RAR] alpha), and LG10068 (ligand for retinoid X receptors [RXRs]), singly or in combination, on the development of lesions were evaluated. Expression of retinoid receptors (RARalpha and RXRalpha) and PPARgamma was determined by western blot analysis. Statistical significance was determined by generalized chi-squared analysis using the GENCAT software program and Bonferroni correction. All P values are two-sided.
Troglitazone (at 10(-5) M) or retinoic acid (at 10(-6) M) markedly inhibited the development of mammary lesions (both P values <.05); however, together they did not enhance the effectiveness of the other. In contrast, LG10068 (at 10(-7) M or 10(-8) M) alone had very little ability to inhibit development of these lesions, but a combination of LG10068 (at 10(-8) M) and troglitazone (at 10(-5) M or 10(-6) M) almost completely inhibited (by 85% and 100%, respectively; both P values <. 05) the development of mammary lesions. The expression of PPARgamma and RXRalpha remained unchanged with the various treatments, whereas the expression of RARalpha was substantially reduced after treatment with the combination of retinoic acid and troglitazone.
To our knowledge, this is the first report showing the possibility of a PPARgamma ligand having chemopreventive activity. Furthermore, an RXR-selective retinoid, LG10068, appears to enhance this activity.
乳腺癌的化学预防是一个活跃的研究领域。最近的体内和体外研究表明，噻唑烷二酮类药物（如曲格列酮）和类视黄醇能够抑制乳腺癌细胞的生长。曲格列酮通过过氧化物酶体增殖物激活受体γ（PPARγ）介导其作用。我们在小鼠乳腺器官培养模型中评估了曲格列酮单独或与类视黄醇联合使用预防7,12 - 二甲基苯并[a]蒽（DMBA）诱导的癌前病变的能力。
用DMBA（2微克/毫升）处理BALB/c小鼠的乳腺，以在器官培养中诱导癌前病变。评估曲格列酮、全反式维甲酸（维甲酸；维甲酸受体[RAR]α的配体）和LG10068（类视黄醇X受体[RXRs]的配体）单独或联合使用对病变发展的影响。通过蛋白质印迹分析确定类视黄醇受体（RARα和RXRα）和PPARγ的表达。使用GENCAT软件程序通过广义卡方分析和Bonferroni校正确定统计学显著性。所有P值均为双侧。
曲格列酮（10⁻⁵ M）或维甲酸（10⁻⁶ M）显著抑制乳腺病变的发展（两个P值均<.05）；然而，它们联合使用时并没有增强彼此的效果。相比之下，LG10068（10⁻⁷ M或10⁻⁸ M）单独抑制这些病变发展的能力很小，但LG10068（10⁻⁸ M）与曲格列酮（10⁻⁵ M或10⁻⁶ M）联合使用几乎完全抑制（分别为85%和100%；两个P值均<.05）乳腺病变的发展。PPARγ和RXRα的表达在各种处理后保持不变，而在用维甲酸和曲格列酮联合处理后，RARα的表达显著降低。
据我们所知，这是第一份显示PPARγ配体具有化学预防活性可能性的报告。此外，一种RXR选择性类视黄醇LG10068似乎增强了这种活性。
