Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosisin HepG2 human hepatoblastoma cells

The signaling mechanism of tamoxifen (TAM)-induced apoptosis was investigat ed in HepG2 human hepatoblastoma cells which do not express the estrogen re ceptor (ER). TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. TAM increased the intracellular conc entration of Ca2+. This effect was completely inhibited by the extracellula r Ca2+ chelation with EGTA. TAM also induced a Mn2+ influx, indicating that TAM activated Ca2+ influx pathways. This action of TAM was significantly i nhibited by flufenamic acid (FA), a known non-selective cation channel bloc ker. Quantitative analysis of apoptosis by flow cytometry revealed that tre atment with either FA or BAPTA, an intracellular Ca2+ chelator, significant ly inhibited TAM-induced apoptosis. These results suggest that intracellula r Ca2+ signals may play a central role in the mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.