Genetic Susceptibility Factors in Aggressive Breast Cancer in African-American Women and the Effects of Carcinogens and Modifiers.
Annual rept. 1 May 98-30 Apr 99
HOWARD UNIV WASHINGTON DC
Pagination or Media Count:
Sigma-2 Receptors are highly expressed in many tumor cell lines. Treatment with sigma-2 selective CB184, CB64D and non-selective agents haloperidol, reduced haloperidol produces cell death by a mode consistent with apoptosis. Apoptosis was confirmed by the TUNEL assay and Annexin V binding. Cell death was quantified by measuring lactate dehydrogenase LDH into culture media. Sigma 2 selective agents CB64D and CB 184 possess similar potency in MCF-7 breast tumor cells and breast tumors with mutations in the p53 tumor Suppressor gene that are phenotypically resistant to certain anti-neoplastic agents MCF-7Adr-, T47D, SKBr3. Doxorubicin and Actinomycin D cytotoxicty are abrogated by inhibitors of caspases Z-VAD-FMK, Y-VAD-CHO, DEVD-CHO, whereas sigma-2 agonist cytotoxicity is unaffected by caspase inhibitors Annexin V binding, LDH release assays. The Sigma-2 agonist CB184 can potentiate cytotoxicity of doxorubicin and actinomycin D in MCF-7 cells and MCF-7Adr- cells. Haloperidol and pentazocine racemic potentiate doxorubicin cell killing in MCF-7Adr- cells. These data suggest different pathways are involved in sigma-2 mediated cytotoxicity as compared with DNA-damaging anti-neoplastics. Further, sigma agonists may have a role in the clinical management of breast cancer, particularly in drug-resistant tumors.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research