We examined the signaling mechanisms involved in the differentiation-inducing activity of lupeol toward B 16 2F2 melanoma cells. α-Melanocyte stimulating hormone (α-MSH), forskolin and dibutyryl cAMP, which are believed to be CAMP-elevating agents and analogues, enhanced lupeol-induced B 16 2F2 cell differentiation. However, H 89, an inhibitor of protein kinase A, completely abolished B 16-2F2 cell differentiation induced by lupeol. Furthermore, we studied the role of mitogen-activated protein kinases (MAPKs) in lupeol-induced B 16 2F2 cell differentiation. U0126, an inhibitor of MAPK kinases, induced B 16 2F2 cell differentiation and enhanced the cell differentiation induced by lupeol. However, SB203580, a selective inhibitor of p 38 MAPK, completely blocked lupeol-induced B 16 2F2 cell differentiation. Western blot analysis revealed that 10 μM lupeol transiently elevated the level of phosphorylation of p 38 MAPK. The phosphorylation of p 38 MAPK was detected on the addition of 1 μM lupeone, another lupane triterpene, but was not induced by 1 μM lupeol. These results suggested that lupeol induced B 16 2F2 cell differentiation through activation of p 38 MAPK, and that the structural differences at C-3 of lupane triterpenes played an important role in the activation of p 38 MAPK.

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