Wen Shao-Hsuan, Su Shey-Chiang, Liou Bo-Huang, Lin Cheng-Hao, Lee Kuan-Rong
1Department of Molecular Medicine and Institute of Life Science, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, 30013 Taiwan, ROC.
Department of Internal Medicine, Puli Christian Hospital, No. 1, Tieshan Road, Puli Township, Nantou, 54546 Taiwan, ROC.
Cancer Cell Int. 2018 Sep 4;18:128. doi: 10.1186/s12935-018-0625-9. eCollection 2018.
Multidrug resistance (MDR) is a major obstacle in breast cancer treatment. The predominant mechanism underlying MDR is an increase in the activity of adenosine triphosphate (ATP)-dependent drug efflux transporters. Sulbactam, a β-lactamase inhibitor, is generally combined with β-lactam antibiotics for treating bacterial infections. However, sulbactam alone can be used to treat infections because it inhibits the expression of ATP-binding cassette (ABC) transporter proteins. This is the first study to report the effects of sulbactam on mammalian cells.
We used the breast cancer cell lines as a model system to determine whether sulbactam affects cancer cells. The cell viabilities in the present of doxorubicin with or without sulbactam were measured by MTT assay. Protein identities and the changes in protein expression levels in the cells after sulbactam and doxorubicin treatment were determined using LC-MS/MS. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to analyze the change in mRNA expression levels of ABC transporters after treatment of doxorubicin with or without sulbactam. The efflux of doxorubicin was measures by the doxorubicin efflux assay.
MTT assay revealed that sulbactam enhanced the cytotoxicity of doxorubicin in breast cancer cells. The results of proteomics showed that ABC transporter proteins and proteins associated with the process of transcription and initiation of translation were reduced. The mRNA expression levels of ABC transporters were also decreased when treated with doxorubicin and sulbactam. The doxorubicin efflux assay showed that sulbactam treatment inhibited doxorubicin efflux.
The combination of sulbactam and doxorubicin enhances the cytotoxicity of doxorubicin in the breast cancer cells by inhibiting the expression of ABC transporter proteins and proteins associated with the process of transcription and initiation of translation, and blocking the efflux of doxorubicin. Co-treatment of doxorubicin and sulbactam can be used in breast cancer treatment to decrease the prescribed dose of doxorubicin to avoid the adverse effects of doxorubicin.
多药耐药性（MDR）是乳腺癌治疗中的主要障碍。MDR的主要潜在机制是三磷酸腺苷（ATP）依赖性药物外排转运蛋白的活性增加。舒巴坦是一种β-内酰胺酶抑制剂，通常与β-内酰胺类抗生素联合用于治疗细菌感染。然而，舒巴坦单独使用也可用于治疗感染，因为它能抑制ATP结合盒（ABC）转运蛋白的表达。这是第一项报道舒巴坦对哺乳动物细胞影响的研究。
我们使用乳腺癌细胞系作为模型系统，以确定舒巴坦是否影响癌细胞。通过MTT法测定在有或无舒巴坦存在的情况下阿霉素处理后的细胞活力。使用液相色谱-串联质谱（LC-MS/MS）确定舒巴坦和阿霉素处理后细胞中的蛋白质身份及蛋白质表达水平的变化。实时逆转录聚合酶链反应（实时RT-PCR）用于分析在有或无舒巴坦的情况下阿霉素处理后ABC转运蛋白mRNA表达水平的变化。通过阿霉素外排试验测定阿霉素的外排。
MTT法显示舒巴坦增强了阿霉素对乳腺癌细胞的细胞毒性。蛋白质组学结果表明ABC转运蛋白以及与转录和翻译起始过程相关的蛋白质减少。用阿霉素和舒巴坦处理后，ABC转运蛋白的mRNA表达水平也降低。阿霉素外排试验表明舒巴坦处理可抑制阿霉素外排。
舒巴坦与阿霉素联合使用可通过抑制ABC转运蛋白以及与转录和翻译起始过程相关的蛋白质的表达，并阻断阿霉素的外排，增强阿霉素对乳腺癌细胞的细胞毒性。阿霉素与舒巴坦联合治疗可用于乳腺癌治疗，以降低阿霉素的规定剂量，避免阿霉素的不良反应。
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