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 signalling processes and current strategies for medical intervention in neoplastic disease are directed towards signal transduction blockade. Redundancy in signalling pathways may mean, however, that a combination of agents is required for the maximal therapeutic benefit. We have explored this idea with regard to the antiestrogen sensitivity of estrogen dependent tumours. Using estrogen receptor (ER) containing tumour cell lines, we have determined whether antiestrogens increase the cytotoxicity of the potent calmodulin inhibitior, 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 effect 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. Further studies strongly suggest that cell death in response to calmodulin inhibition is the result of metabolic disruption and that for GH(3) cells, this is enhanced by antiestrogen treatment.
Newton
C J
CJ
Molecular Pharmacology, Faculty of Health, University of Hull, UK. cjnewton@compuserve.com
Eycott
K
K
Green
V
V
Atkin
S L
SL
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002147:Calmodulin; D020847:Estrogen Receptor Modulators; D007093:Imidazoles; D011960:Receptors, Estrogen; D000077267:Fulvestrant; C031938:calmidazolium; D004958:Estradiol