Mukherjee Sudeshna, Gupta Payal, Ghosh Sayan, Choudhury Sreetama, Das Ankur, Ahir Manisha, Adhikary Arghya, Chattopadhyay Sreya
Department of Physiology, University of Calcutta, Kolkata, India.
Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India.
J Nutr Biochem. 2023 May;115:109283. doi: 10.1016/j.jnutbio.2023.109283. Epub 2023 Feb 14.
One of the key biochemical features that distinguish a cancer cell from normal cells is its persistent pro-oxidative state that leads to intrinsic oxidative stress. Malignant cells have evolved sophisticated adaptation systems that involve high dependency on antioxidant functions and upregulation of pro-survival molecules to counteract the deleterious effects of reactive species and to maintain dynamic redox balance. This situation renders them vulnerable to further oxidative challenges by exogenous agents. In the present study, we advocated that pomegranate polyphenols act as pro-oxidants and trigger ROS-mediated apoptosis in cancer cells. With the help of both in vitro and in vivo models, we have established that pomegranate fruit extract (PFE) can cause a significant reduction in tumor proliferation while leaving normal tissues and cells unharmed. Administration of PFE (0.2% v/v) in Erhlich's ascites carcinoma-bearing mice for 3 weeks, inhibited the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element signaling cascade, increased intracellular reactive oxygen species content, altered glutathione cycle thereby activating reactive oxygen species-induced apoptotic pathway in Erhlich's ascites carcinoma cells. Moreover, PFE mitigated epithelial to mesenchymal transition and migration in triple negative breast cancer cells (MDA-MB 231 cells) by down-regulating nuclear factor kappa light-chain-enhancer of activated B cells. Pre-treatment of tumor cells with N-acetyl cysteine protected these cells from undergoing PFE-induced apoptosis while siRNA-mediated silencing of Nuclear factor (erythroid-derived 2)-like 2 and nuclear factor kappa light-chain-enhancer of activated B cells in tumor cells increased the cytotoxic potential and pro-oxidative activity of PFE, indicating a clear role of these transcription factors in orchestrating the anticancer/pro-oxidative properties of PFE. The seminal findings provided may be exploited to develop potential therapeutic targets for selective killing of malignant cells.
癌细胞与正常细胞相区别的关键生化特征之一是其持续的促氧化状态，这种状态会导致内在的氧化应激。恶性细胞已经进化出复杂的适应系统，该系统高度依赖抗氧化功能并上调促生存分子，以抵消活性物质的有害影响并维持动态的氧化还原平衡。这种情况使它们容易受到外源性物质进一步氧化挑战的影响。在本研究中，我们主张石榴多酚作为促氧化剂，触发癌细胞中活性氧介导的细胞凋亡。借助体外和体内模型，我们已证实石榴果实提取物（PFE）可显著降低肿瘤增殖，同时不损害正常组织和细胞。给荷艾氏腹水癌小鼠腹腔注射3周PFE（0.2% v/v），抑制了核因子（红系衍生2）样2-抗氧化反应元件信号级联，增加了细胞内活性氧含量，改变了谷胱甘肽循环，从而激活了艾氏腹水癌细胞中活性氧诱导的凋亡途径。此外，PFE通过下调活化B细胞的核因子κB轻链增强子，减轻了三阴性乳腺癌细胞（MDA-MB 231细胞）的上皮-间质转化和迁移。用N-乙酰半胱氨酸预处理肿瘤细胞可保护这些细胞免受PFE诱导的凋亡，而siRNA介导的肿瘤细胞核因子（红系衍生2）样2和活化B细胞核因子κB轻链增强子沉默增加了PFE的细胞毒性潜力和促氧化活性，表明这些转录因子在协调PFE的抗癌/促氧化特性中具有明确作用。所提供的开创性发现可用于开发选择性杀死恶性细胞的潜在治疗靶点。
