gdc-0449 and evodiamine

The hedgehog (Hh) signalling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis and progression of a variety of aggressive human cancers including skin cancer. Despite its importance, little is known about its role in photoageing, a type of UV-induced skin lesions. In this study, we investigated the involvement of Hh signalling in the photoageing process as well as the use of an Hh-regulating alkaloid compound as a novel therapeutic drug to regulate photoageing in keratinocytes. We found that UVB induced Hh signalling by the expression of Hh ligands and Hh-mediated transcription factors, respectively. Moreover, UVB-induced Hh activation relied on mitogen-activated protein kinase (p38, ERK and JNK) activity and inflammatory responses (upregulation of COX-2, IL-1β, IL-6 and TNF-α), resulting in premature senescence and photoageing in vitro and in vivo. Notably, a selected Hh inhibitor, evodiamine, mediated photoageing blockade in a mouse skin model. Taken together, our findings demonstrated that Hh signalling is associated with UVB-induced photoageing, while pharmacological inhibition of Hh signalling significantly reduced experimental photoageing, indicating its potential for use as a therapeutic target for this disease.

Topics: Aging; Anilides; Animals; Cell Line; Cyclooxygenase 2; Cytokines; Drug Evaluation, Preclinical; Flavonoids; Gene Expression Regulation; Hedgehog Proteins; Humans; Inflammation; MAP Kinase Signaling System; Mice; Pyridines; Quinazolines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Skin Aging; Tissue Inhibitor of Metalloproteinase-1; Ultraviolet Rays