Department of Biophysics, Bose Institute, P 1/12 CIT Scheme VII M, Kolkata 700 054, WB, India.
Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake City, Kolkata 700 098, WB, India.
Biochem Pharmacol. 2018 Oct;156:322-339. doi: 10.1016/j.bcp.2018.08.041. Epub 2018 Aug 29.
Potent anticancer activity coupled with absence of toxicity at therapeutic dose established the glycolytic metabolite, methylglyoxal, as a promising candidate against malignant neoplasia. In this preclinical study we illustrate the applicability of methylglyoxal in formulating an optimally designed combination regimen with chemotherapeutic drugs against breast cancer. Results demonstrated a synergistic augmentation in doxorubicin and cisplatin mediated cytotoxicity in human breast cancer cell lines MDA MB 231 & MCF 7 with methylglyoxal co-treatment at metronomic concentrations. The cell death due to combination treatment was significantly prevented by N-Acetylcysteine and the synergistic effects were attenuated in presence of inhibitors for apoptosis and necroptosis, in MDA MB 231 and MCF 7 cells, respectively. Additionally, acridine orange staining and immunoblotting with LC3B antibody indicated the suppression of doxorubicin induced autophagy flux with methylglyoxal co-treatment. This report documents for the first time the preferential targeting of breast cancer stem cells by methylglyoxal. Combination treatment with doxorubicin or cisplatin hindered mammosphere forming efficiency and inclusively eliminated both cancer stem as well as non-stem cancer cells. The synergistic effect was validated in Ehrlich mammary carcinoma cell induced murine ascites model and the combination advantage in vivo was achieved without any additional deleterious effect to liver and kidney. Our present study evidences the implications of methylglyoxal inclusion in adjuvant multimodal chemotherapeutics against breast cancer and offers noteworthy insights into the possible outcome.
在治疗剂量下无毒性而具有强大抗癌活性，使糖解代谢物甲基乙二醛成为治疗恶性肿瘤的有前途的候选药物。在这项临床前研究中，我们说明了将甲基乙二醛用于制定与化疗药物联合的最佳设计方案来治疗乳腺癌的适用性。结果表明，在低剂量下与甲基乙二醛共同处理可协同增强多柔比星和顺铂对人乳腺癌细胞系 MDA MB 231 和 MCF 7 的细胞毒性。用 N-乙酰半胱氨酸处理可显著预防因联合治疗而导致的细胞死亡，并且在 MDA MB 231 和 MCF 7 细胞中，凋亡和坏死抑制剂的存在可减弱协同作用。此外，吖啶橙染色和 LC3B 抗体的免疫印迹表明，与多柔比星联合处理可抑制多柔比星诱导的自噬流。这是首次报道甲基乙二醛优先靶向乳腺癌干细胞。与多柔比星或顺铂联合治疗可降低乳腺球体形成效率，并同时消除癌症干细胞和非干细胞癌细胞。协同作用在艾氏腹水癌诱导的小鼠腹水模型中得到了验证，并且在体内联合治疗没有对肝脏和肾脏造成任何额外的有害影响。我们的研究证明了将甲基乙二醛纳入辅助多模式化疗治疗乳腺癌的意义，并为可能的结果提供了有价值的见解。
