Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosis

Abstract

Introduction Estrogen deprivation using aromatase inhibitors is one of the standard treatments for postmenopausal women with estrogen receptor (ER)-positive breast cancer. However, one of the consequences of prolonged estrogen suppression is acquired drug resistance. Our group is interested in studying antihormone resistance and has previously reported the development of an estrogen deprived human breast cancer cell line, MCF-7:5C, which undergoes apoptosis in the presence of estradiol. In contrast, another estrogen deprived cell line, MCF-7:2A, appears to have elevated levels of glutathione (GSH) and is resistant to estradiol-induced apoptosis. In the present study, we evaluated whether buthionine sulfoximine (BSO), a potent inhibitor of glutathione (GSH) synthesis, is capable of sensitizing antihormone resistant MCF-7:2A cells to estradiolinduced apoptosis.

Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time

“…Before gene expression microarray studies were carried out, the estrogen-dependent WS8 (29-31), ED-resistant but apoptosis-refractory 2A (25,30,31), and apoptosis-sensitive 5C cells (24,29,32) were characterized to confirm previously reported growth responses, biomarker status, and estrogen response element (ERE) -regulated transcriptional activity (SI Results and Discussion, SI Methods, and Fig. S1).…”

“…When cells were grown under long-term estrogendeprived conditions (>1 y), cells lost their dependency on estrogen for proliferation but maintained expression of ER. Subsequent studies of E 2 action on the growth of long-term estrogen-deprived MCF-7 cells in vitro at high (23) and low concentrations in vitro and in vivo (24,25) indicated that the concept of "an estrogen purge" (19) to destroy antihormone-resistant cells could be applied to the treatment of breast cancer. This concept has now been translated to clinical trials.…”

“…By describing and defining these molecular events, refractory cells may be manipulated to respond to estrogen-induced apoptosis. To begin to address the question, we have developed a series of MCF-7 variants that are either estrogen-dependent for growth (MCF-7:WS8 cells) (29)(30)(31) or resistant to estrogen deprivation (ED) and refractory (MCF-7:2A) (25,30,31) or sensitive (MCF-7:5C) (24,29,32) to E 2 -induced apoptosis. We previously reported changes in gene expression among these cell lines by Affymetrix-based microarray analysis under estrogen-free conditions (33).…”

Estrogen-Induced Apoptosis in Breast Cancer Cells: Translation to Clinical Relevance

“…Changes in GSH homeostasis have been implicated in the etiology and progression of some diseases and breast cancer (Townsend et al 2003) and studies have shown that elevated levels of GSH prevent apoptotic cell death whereas depletion of GSH facilitates apoptosis (Anderson et al 1999). Our laboratory has found evidence which suggests that GSH participates in retarding apoptosis in antihormoneresistant MCF-7:2A human breast cancer cells, which have ~60% elevated levels of GSH compared to wild-type MCF-7 cells and unable to undergo estrogen-induced apoptosis within 1 week unlike MCF-7:5C cells, and that depletion of GSH by 100 µM of L-buthionine sulfoximine (BSO), a potent inhibitor of glutathione biosynthesis, sensitizes these resistant cells to estradiol-induced apoptosis (Lewis-Wambi et al 2008). However, the question arises as to the actual mechanism of the apoptotic trigger mediated by the ER complex.…”

Estrogen Reduces Caspase-3 Expression in the Inner Ear of Guinea Pigs Exposed to Simulated Microgravity and Inboard Noises of Spaceship

“…It has been reported that oestrogen protects pancreatic beta [11] , retina ganglion [12] , neuronal [13] , bone [14] , and heart [15] cells via inhibition of apoptosis. However, oestrogen also plays a role in increasing apoptosis in other cell types, such as osteoclasts [16] , breast cancer cells [17] , and leukaemia cells [18] . For human hearing, oestrogen seems to have protective effects [19] .…”