Chang Andy, Yeung Steven, Thakkar Arvind, Huang Kevin M, Liu Mandy M, Kanassatega Rhye-Samuel, Parsa Cyrus, Orlando Robert, Jackson Edwin K, Andresen Bradley T, Huang Ying
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California.
Department of Clinical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, California.
Cancer Prev Res (Phila). 2015 Jan;8(1):27-36. doi: 10.1158/1940-6207.CAPR-14-0193. Epub 2014 Nov 3.
The stress-related catecholamine hormones and the α- and β-adrenergic receptors (α- and β-AR) may affect carcinogenesis. The β-AR GRK/β-arrestin biased agonist carvedilol can induce β-AR-mediated transactivation of the EGFR. The initial purpose of this study was to determine whether carvedilol, through activation of EGFR, can promote cancer. Carvedilol failed to promote anchorage-independent growth of JB6 P(+) cells, a skin cell model used to study tumor promotion. However, at nontoxic concentrations, carvedilol dose dependently inhibited EGF-induced malignant transformation of JB6 P(+) cells, suggesting that carvedilol has chemopreventive activity against skin cancer. Such effect was not observed for the β-AR agonist isoproterenol and the β-AR antagonist atenolol. Gene expression, receptor binding, and functional studies indicate that JB6 P(+) cells only express β2-ARs. Carvedilol, but not atenolol, inhibited EGF-mediated activator protein-1 (AP-1) activation. A topical 7,12-dimethylbenz(α)anthracene (DMBA)-induced skin hyperplasia model in SENCAR mice was utilized to determine the in vivo cancer preventative activity of carvedilol. Both topical and oral carvedilol treatment inhibited DMBA-induced epidermal hyperplasia (P < 0.05) and reduced H-ras mutations; topical treatment being the most potent. However, in models of established cancer, carvedilol had modest to no inhibitory effect on tumor growth of human lung cancer A549 cells in vitro and in vivo. In conclusion, these results suggest that the cardiovascular drug carvedilol may be repurposed for skin cancer chemoprevention, but may not be an effective treatment of established tumors. More broadly, this study suggests that β-ARs may serve as a novel target for cancer prevention.
与应激相关的儿茶酚胺激素以及α和β肾上腺素能受体（α-AR和β-AR）可能影响癌症发生。β-AR GRK/β-抑制蛋白偏向性激动剂卡维地洛可诱导β-AR介导的表皮生长因子受体（EGFR）反式激活。本研究的最初目的是确定卡维地洛是否通过激活EGFR促进癌症。卡维地洛未能促进JB6 P(+)细胞的非锚定依赖性生长，JB6 P(+)细胞是一种用于研究肿瘤促进作用的皮肤细胞模型。然而，在无毒浓度下，卡维地洛剂量依赖性地抑制表皮生长因子（EGF）诱导的JB6 P(+)细胞恶性转化，表明卡维地洛具有预防皮肤癌的化学预防活性。β-AR激动剂异丙肾上腺素和β-AR拮抗剂阿替洛尔未观察到这种效果。基因表达、受体结合和功能研究表明，JB6 P(+)细胞仅表达β2-AR。卡维地洛而非阿替洛尔抑制EGF介导的激活蛋白-1（AP-1）激活。利用SENCAR小鼠的局部7,12-二甲基苯并(α)蒽（DMBA）诱导的皮肤增生模型来确定卡维地洛的体内癌症预防活性。局部和口服卡维地洛治疗均抑制DMBA诱导的表皮增生（P<0.05）并减少H-ras突变；局部治疗效果最强。然而，在已建立的癌症模型中，卡维地洛对人肺癌A549细胞的体外和体内肿瘤生长具有适度或无抑制作用。总之，这些结果表明心血管药物卡维地洛可重新用于皮肤癌化学预防，但可能不是已建立肿瘤的有效治疗方法。更广泛地说，本研究表明β-AR可能是癌症预防的新靶点。
