Hypnophilin (HNP) is a sesquiterpene that is isolated from Lentinus cf. strigosus and has cytotoxic activities. Here, we studied the calcium signaling and cytotoxic effects of HNP in UACC-62 cells, a human skin melanoma cell line. HNP was able to increase the intracellular calcium concentration in UACC-62 cells, which was blocked in cells stimulated in Ca2+-free media. HNP treatment with BAPTA-AM, an intracellular Ca2+ chelator, caused an increase in calcium signals. HNP showed cytotoxicity against UACC-62 cells in which it induced DNA fragmentation and morphological alterations, including changes in the nuclear chromatin profile and increased cytoplasmatic vacuolization, but it had no effect on the plasma membrane integrity. These data suggest that cytotoxicity in UACC-62 cells, after treatment with HNP, is associated with Ca2+ influx. Together, these findings suggest that HNP is a relevant tool for the further investigation of new anticancer approaches. (c) 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:479-485, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21507