Cilostazol, a licensed clinical drug for the treatment of intermittent claudication, is a phosphodiesterase (PDE) inhibitor that selectively inhibits PDE3, a cAMP-degrading enzyme, thus elevating levels of intracellular cAMP. It has been reported that pigment production by melanocytes both tans the skin and protects against skin cancers. The effects of cilostazol in melanogenesis are as yet unknown. In this study, treatment with cilostazol was found to promote the production of melanin as well as increase both Tyrosinase enzymatic activity and expression of the Tyrosinase gene. Importantly, we also found that cilostazol led to increased expression of the microphthalmia-associated transcription factor (MITF), the "master regulator" of both melanocyte differentiation and pigment production. Interestingly, knockdown of MITF using siRNA abolished the effects of cilostazol in melanogenesis, thereby suggesting that MITF might play a critical role in melanogenesis. Increased expression of MITF was abolished by treatment with H-89, a specific protein kinase A (PKA) inhibitor, thereby suggesting that the PICA pathway plays a critical role in cilostazol-induced expression of MITF. Cilostazol in fact enhanced expression of p-CREB, which was inhibited by H-89. Moreover, this cilostazol-induced increase in expression of MITF was inhibited by downregulation of CREB using CREB siRNA. These data suggest that induction of MITF via the PKA/CREB pathway plays a critical role in cilostazol-induced production of melanin in B16-F10 melanoma cells. (C) 2013 Elsevier Inc. All rights reserved.