Response of estrogen receptor containing tumour cells to pure antiestrogens and the calmodulin inhibitor, calmidzolium chloride

Cell survival is dependent on both external and internally generated signal ling processes and current strategies for medical intervention in neoplasti c disease are directed towards signal transduction blockade. Redundancy in signalling pathways may mean, however, that a combination of agents is requ ired for the maximal therapeutic benefit. We have explored this idea with r egard to the antiestrogen sensitivity of estrogen dependent tumours. Using estrogen receptor (ER) containing tumour cell lines, we have determined whe ther antiestrogens increase the cytotoxicity of the potent calmodulin inhib itor, calmidzolium chloride (CCl). For the pituitary tumour cell line GH(3) , CCl induces a form of apoptotic cell death and co-treatment with the pure antiestrogen, ZM 182780, enhances sensitivity to the calmodulin inhibitor, by at least two fold. In contrast to the pure steroidal antiestrogens, the triphenylethylenes, tamoxifen and 4-hydroxytamoxifen give no enhancing eff ect on CCl induced cell death. Although CCl induces apoptosis of several ER containing breast cancer cell lines, unlike the pituitary tumour cells, ZM 182780 is unable to increase their sensitivity to calmodulin inhibition. F urther studies strongly suggest that cell death in response to calmodulin i nhibition is the result of metabolic disruption and that for GH3 cells, thi s is enhanced by antiestrogen treatment. (C) 2000 Elsevier Science Ltd. All rights reserved.