Mechanisms of tamoxifen-induced apoptosis.
Tamoxifen (TAM) has been used in the treatment of breast cancer for over a decade. The observed clinical efficacy of TAM has been attributed to both growth arrest and induction of apoptosis within the breast cancer cells. Although the primary mechanism of action of TAM is believed to be through the inhibition of estrogen receptor (ER), research over the years has indicated that additional, non-ER-mediated mechanisms exist. These include modulation of signaling proteins such as protein kinase C (PKC), calmodulin, transforming growth factor-beta (TGFbeta), and the protooncogene c-myc. Recent studies, including those from our laboratory, have implicated the role of caspases and mitogen-activated protein kinases (MAPK), including c-Jun N-terminal kinase (JNK) and p38 in TAM-induced apoptotic signaling. Oxidative stress, mitochondrial permeability transition (MPT), ceramide generation as well as changes in cell membrane fluidity may also play important roles in TAM-induced apoptosis. These various signaling pathways underlying TAM-induced apoptosis will be reviewed in this article.
Mandlekar
S
S
Department of Drug Metabolism and Pharmacokinetics, DuPont Pharmaceuticals Company, Newark, DE 19711, USA. sandhya.mandlekar@dupontpharma.com
Kong
A N
AN
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System; D008928:Mitochondria / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D002147:Calmodulin; D002518:Ceramides; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium