title: Potential of l-buthionine sulfoximine to enhance the apoptotic action of estradiol to reverse acquired antihormonal resistance in metastatic breast cancer.
abstract: L-Buthionine sulfoximine (BSO) is a potent inhibitor of glutathione biosynthesis and studies have shown that it is capable of enhancing the apoptotic effects of several chemotherapeutic agents. Previous studies have shown that long-term antihormonal therapy leads to acquired drug resistance and that estrogen, which is normally a survival signal, is a potent apoptotic agent in these resistant cells. Interestingly, we have developed an antihormone-resistant breast cancer cell line, MCF-7:2A, which is resistant to estrogen-induced apoptosis but has elevated levels of glutathione. In the present study, we examined whether BSO is capable of sensitizing antihormone-resistant MCF-7:2A cells to estrogen-induced apoptosis. Our results showed that treatment of MCF-7:2A cells with 1nM E2 plus 100muM BSO combination for 1 week reduced the growth of these cells by almost 80-90% whereas the individual treatments had no significant effect on growth. TUNEL and 4',6-diamidino-2-phenylindole (DAPI) staining showed that the inhibitory effect of the combination treatment was due to apoptosis. Our data indicates that glutathione participates in retarding apoptosis in antihormone-resistant human breast cancer cells and that depletion of this molecule by BSO may be critical in predisposing resistant cells to estrogen-induced apoptosis.
authors.affiliation: Department of Medical Sciences, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, United States.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Lewis-Wambi
authors.forename: Ramona
authors.initials: R
authors.lastname: Swaby
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D019328:Buthionine Sulfoximine / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol; D019328:Buthionine Sulfoximine; D005978:Glutathione