Anticlusterin treatment of breast cancer cells increases the sensitivities of chemotherapy and tamoxifen and counteracts the inhibitory action of dexamethasone on chemotherapy-induced cytotoxicity.
BACKGROUND
Overexpression of the apoptosis-related protein clusterin is associated with breast cancer development and tumor progression. We describe the use of clusterin-specific antisense oligonucleotides and antibodies to sensitize breast carcinoma cells to anticancer drugs routinely used in breast cancer therapy.


METHODS
MCF-7 and MDA-MB-231 cells were treated with the oligonucleotide or antibody, chemotherapeutic agents (doxorubicin or paclitaxel), tamoxifen, or with combinations of these.


RESULTS
Treatments that include antisense clusterin oligonucleotide or antibody to clusterin have been shown to reduce the number of viable cells more effectively than treatment with the drugs alone. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. However, anticlusterin treatment increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids, suggesting a possible role for these proteins in glucocorticoid-mediated survival.


CONCLUSIONS
These data suggest that combined treatment with antibodies to clusterin or antisense clusterin oligodeoxynucleotides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast cancer cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses.
Redondo
Maximino
M
Department of Biochemistry, Hospital Costa del Sol, Carretera de Cádiz Km 187, 29600 Marbella, Málaga, Spain. mredondo@hcs.es
Téllez
Teresa
T
Roldan
Maria J
MJ
Serrano
Alfonso
A
García-Aranda
Maria
M
Gleave
Martin E
ME
Hortas
Maria L
ML
Morell
Miguel
M
D000912:Antibodies, Neoplasm / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051152:Clusterin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D006801:Humans; D020287:In Situ Nick-End Labeling; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; C495242:CLU protein, human; D051152:Clusterin; D005938:Glucocorticoids; D016376:Oligonucleotides, Antisense; D013629:Tamoxifen; D003907:Dexamethasone; D004317:Doxorubicin; D017239:Paclitaxel