Abstract
Glutamine provides cancer cells with the energy required to synthesize macromolecules. Methods which block glutamine metabolism in treatment of breast cancer inhibit oncogenic transformation and tumor growth. We investigated whether inhibiting glutamine metabolism produces effects that are synergistic with those produced by drugs which damage DNA in triple-negative breast cancer cells. HCC1937 and BT-549 breast cancer cells were co-treated with either cisplatin or etoposide in combination with BPTES (a specific inhibitor of glutaminase 1) or exposure to a glutamine-free medium, and the cell proliferation and cell apoptosis were measured by flow cytometry, immunoblotting studies, and CCK-8 assays. The results showed that both glutamine deprivation and BPTES pretreatments increased the toxic effects of cisplatin and etoposide on HCC1937 cells, as demonstrated by their reduced proliferation, increased expression of apoptosis-related proteins (cleaved-PARP, cleaved-caspase 9, and cleaved-caspase 3) and decreased Bcl-2/BAX ratio. However, in BT-549 cells, glutamine deprivation and BPTES treatment increased etoposide-induced apoptosis only when used with higher concentrations of etoposide, and the effect on cisplatin-induced apoptosis was minimal. These results suggest that the anti-cancer effects produced by a combined approach of inhibiting glutamine metabolism and administering common chemotherapeutic agents correlate with the tumor cell type and specific drugs being administered.
Highlights
Breast cancer is the second most common cancer worldwide, and women with this disease exhibit a high rate of disease relapse [1]
HCC1937 and BT-549 cells were treated with various concentrations of etoposide or cisplatin for 48 h, after which their viability was measured by use of the CCK-8 assay
HCC1937 and BT-549 cells cultured in glutamine-free medium for 24 h displayed greater inhibition of cisplatin- and etoposide-induced cell proliferation than did cells that had not been cultured in glutamine-free medium, suggesting the synergistic effects of these treatments
Summary
Breast cancer is the second most common cancer worldwide, and women with this disease exhibit a high rate of disease relapse [1]. Triple-negative breast cancer is the most aggressive type of the disease and the only class treated with chemotherapy alone [2]. Glutamine is a non-essential amino acid which serves as a precursor for the synthesis of many amino acids, proteins, and nucleotides It participates in gluconeogenesis and helps to provide oxidative fuel (NADPH and NADH) for rapidly proliferating cells and tissues, as well as for glutathione synthesis [5]. Various inhibitors of glutaminase and glutamate dehydrogenase enzymes, as www.impactjournals.com/oncotarget well as glutamine transporters, have been proven effective for inhibiting the growth of cancer cells [6,7,8]. Several studies have shown that BPTES can significantly inhibit the growth of xenograft tumors initiated with c-Myc-transformed lymphoma cells [16], and induce apoptosis in IMR90-ERMYC and HA1E-MYCER cells in a MYC-dependent manner. Glutamine deprivation has been proven to induce cell death or cause synergistic effects in various types of cancer cells when used in combination with chemotherapeutic drugs [18,19,20,21,22,23,24,25]
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