Thursday, November 21, 2024
11/21/2024
Skin cancer, particularly non-melanoma skin cancer, is by far the most common malignancy in the US. Overexposure to ultraviolet (UV) radiation is a main factor causing skin cancer, via inducing DNA damage, inflammation, and immunosuppression. The β-adrenergic receptor (β-AR) antagonist (β-blocker) carvedilol, a commonly used drug for cardiovascular disorders, has shown promising activity in preventing UV-induced skin cancer in vitro and in vivo. However, as a highly potent β-blocker, systemic absorbtion of carvedilol may cause unwanted cardiovascular effects such as bradycardia and hypotention. To overcome this obstacle, two strategies are applied: (1) development of a skin targeting nanodelivery system, and (2) examination of the effects of the non-β-blocking R-carvedilol enantiomer, because carvedilol is a racemic mixture consisting of the β-blocking S- carvedilol and non-β-blocking R-carvedilol in 1:1 ratio. Preliminary data indicate that topical delivery of carvedilol loaded nano-transfersome was able to effectively prevent skin cancer without systemic absorption. Additional data indicate that β-blockade is dispensable for carvedilol's cancer preventive activity. Further preliminary studies indicate that R-carvedilol, although not a β-blocker, is effective in preventing UV-induced immunosuppression and skin carcinogenesis without affecting blood pressure. Importantly, both R- and S- carvedilol inhibit ryanodine receptors (RyRs) by reducing the opening time of this intracellular calcium channel, and further preliminary data suggest that reducing RyR opening activity represents a previously unexplored mechanism for skin cancer prevention. Thus, the overall objective of this application is to determine the molecular target for carvedilol-mediated chemoprevention and examine a novel nanodelivery system of R- carvedilol as an effective and safe approach for skin cancer prevention. Aim 1 is to test the hypothesis that carvedilol prevents cancer independently of β-blockade. Aim 2 is to test the hypothesis that reducing RyR activity mediates carvedilol's cancer preventative activity. Aim 3 is test the hypothesis that R-carvedilol can be formulated in nano-transfersome gel which can be safely and repeatedly applied to the skin without significant systemic absorption. Since carvedilol is an FDA-approved agent, we anticipate the outcomes from this project will be readily translated into a cancer preventive regimen for healthy human subjects or individuals with weakened immune system. Importantly, R-carvedilol, lacking β-blocking activity, is expected to prevent cancer without cardiovascular disturbance, and therefore should be an excellent drug for skin cancer chemoprevention.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
