Carvedilol inhibits EGF-mediated JB6 P+ colony formation through a mechanism independent of adrenoceptors.

ABSTRACT: Carvedilol is reported to prevent cancers in humans and animal models. However, a molecular mechanism has yet to be established, and the extent to which other ?-blockers are chemopreventive remains relatively unknown. A comparative pharmacological approach was utilized with the expectation that a mechanism of action could be devised. JB6 Cl 41-5a (JB6 P+) murine epidermal cells were used to elucidate the chemopreventative properties of ?-blockers, as JB6 P+ cells recapitulate in vivo tumor promotion and chemoprevention. The initial hypothesis was that ?-blockers that are GRK/?-arrestin biased agonists, like carvedilol, are chemopreventive. Sixteen ?-blockers of different classes, isoproterenol, and HEAT HCl were individually co-administered with epidermal growth factor (EGF) to JB6 P+ cells to examine the chemopreventative properties of each ligand. Cytotoxicity was examined to ensure that the anti-transformation effects of each ligand were not due to cellular growth inhibition. Many of the examined ?-blockers suppressed EGF-induced JB6 P+ cell transformation in a non-cytotoxic and concentration-dependent manner. However, the IC50 values are high for the most potent inhibitors (243, 326, and 431 nM for carvedilol, labetalol, and alprenolol, respectively) and there is no correlation between pharmacological properties and inhibition of transformation. Therefore, the role of ?1- and ?2-adrenergic receptors (AR) was examined by standard competition assays and shRNA targeting ?2-ARs, the only ?-AR expressed in JB6 P+ cells. The results reveal that pharmacological inhibition of ?1- and ?2-ARs and genetic knockdown of ?2-ARs did not abrogate carvedilol-mediated inhibition of EGF-induced JB6 P+ cell transformation. Furthermore, topical administration of carvedilol protected mice from UV-induced skin damage, while genetic ablation of ?2-ARs increased carvedilol-mediated effects. Therefore, the prevailing hypothesis that the chemopreventive property of carvedilol is mediated through ?-ARs is not supported by this data.

SUBMITTER: Cleveland KH 

PROVIDER: S-EPMC6527222 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature