TY - JOUR
T1 - Potential of l-buthionine sulfoximine to enhance the apoptotic action of estradiol to reverse acquired antihormonal resistance in metastatic breast cancer
AU - Lewis-Wambi, Joan S.
AU - Swaby, Ramona
AU - Kim, Helen
AU - Jordan, V. Craig
N1 - Funding Information:
This work was supported by the Department of Defense Breast Program under award number BC050277 Center of Excellence (VCJ); Fox Chase Cancer Center Core Grant NIH P30 CA006927 (VCJ); Weg Fund of Fox Chase Cancer Center (VCJ); the American Cancer Society Grant IRG-92-027-14 (JSLW); the Hollenbach Family Fund (JSLW), and the NIH Career Development Grant 1K01CA120051-01A2 (JSLW). The views and opinions of the author(s) do not reflect those of the US Army or the Department of Defense.
PY - 2009/3
Y1 - 2009/3
N2 - 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 1 nM E2 plus 100 μM 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.
AB - 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 1 nM E2 plus 100 μM 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.
KW - Antihormone resistance
KW - Apoptosis
KW - Breast cancer
KW - Glutathione
KW - Low dose estrogen therapy
KW - l-Buthionine sulfoximine
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U2 - 10.1016/j.jsbmb.2008.12.016
DO - 10.1016/j.jsbmb.2008.12.016
M3 - Article
C2 - 19167492
AN - SCOPUS:62949186374
SN - 0960-0760
VL - 114
SP - 33
EP - 39
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 1-2
ER -