Genetic Susceptibility Factors in Aggressive Breast Cancer in African- American Women and the Effects of Carcinogens and Modifiers

摘要

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-7/Adr-, 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-7/Adr- cells. Haloperidol and pentazocine (racemic) potentiate doxorubicin cell killing in MCF-7/Adr- 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.