Chen Lian, Cui Hengmin, Fang Jing, Deng Huidan, Kuang Ping, Guo Hongrui, Wang Xun, Zhao Ling
College of Veterinary Medicine, Sichuan Agricultural University, Ya'an 625014, China.
Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Ya'an 625014, China.
Oncotarget. 2016 Aug 23;7(34):54691-54701. doi: 10.18632/oncotarget.10579.
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.
谷氨酰胺为癌细胞提供合成大分子所需的能量。在乳腺癌治疗中阻断谷氨酰胺代谢的方法可抑制致癌转化和肿瘤生长。我们研究了抑制谷氨酰胺代谢是否会产生与损伤三阴性乳腺癌细胞中DNA的药物所产生的效应协同的作用。将HCC1937和BT - 549乳腺癌细胞与顺铂或依托泊苷联合BPTES（谷氨酰胺酶1的特异性抑制剂）共同处理，或暴露于无谷氨酰胺培养基中，通过流式细胞术、免疫印迹研究和CCK - 8测定法测量细胞增殖和细胞凋亡。结果表明，谷氨酰胺剥夺和BPTES预处理均增加了顺铂和依托泊苷对HCC1937细胞的毒性作用，表现为细胞增殖减少、凋亡相关蛋白（裂解的PARP、裂解的半胱天冬酶9和裂解的半胱天冬酶3）表达增加以及Bcl - 2/BAX比值降低。然而，在BT - 549细胞中，谷氨酰胺剥夺和BPTES处理仅在与较高浓度的依托泊苷联合使用时增加依托泊苷诱导的凋亡，而对顺铂诱导的凋亡影响最小。这些结果表明，抑制谷氨酰胺代谢与施用常用化疗药物的联合方法所产生的抗癌作用与肿瘤细胞类型和所施用的特定药物相关。
