Department of Physiology, Center for Nanoscience and Nanotechnology, and Centre with Potential for Excellence in Particular Area (CPEPA), University of Calcutta , Kolkata , India.
Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology , Kolkata , India.
Free Radic Res. 2019 Oct;53(9-10):944-967. doi: 10.1080/10715762.2019.1655559. Epub 2019 Oct 2.
The major drawback of anticancer therapy is the development of resistance against drugs and radiation at the later phase of treatment which may lead to recurrences of the disease. Therefore, strategy was taken to enhance radiation sensitivity of lung (A549) and liver (HepG2) carcinoma cells by treatment with ferulic acid (FA) prior to irradiation. FA pre-treatment initially decreased reactive oxygen species (ROS) level in carcinoma cells which induced reductive stress and cytostasis. To overcome this stress, cellular mechanism increased the Keap1 level to down-regulate nuclear localisation of Nrf2 and its dependent antioxidant system. The antioxidant system reached the lowest level after 3 and 6 h of FA treatment in A549 and HepG2 cells respectively. As endogenous ROS were still being generated at same rate, ROS level was clearly higher than control which changed the reductive stress to oxidative stress. Exposure to γ-radiation in this condition further increased ROS level and caused radio-sensitisation of carcinoma cells. Combination of irradiation (IR) and FA activated mitochondrial apoptotic pathway and concomitantly inhibited the cell cycle progression and survival pathway over the IR group. Moreover, the combination treatment showed significant tumour regression, caspase 3 activation and nuclear fragmentation in tumour tissue compared to radiation alone. In contrast, FA pre-treatment protected peripheral blood mononuclear cells (PBMC) and normal lung fibroblast WI38 cells from radiation damage. Together, combination treatment offers effective strategy of killing cancer cells and demonstrates its potential for increasing the efficacy of radio-therapy.
癌症治疗的主要缺点是在治疗后期对药物和辐射产生耐药性，这可能导致疾病复发。因此，我们采取了策略，通过在辐照前用阿魏酸（FA）处理来提高肺癌（A549）和肝癌（HepG2）癌细胞的辐射敏感性。FA 预处理最初降低了癌细胞中的活性氧（ROS）水平，从而诱导还原性应激和细胞停滞。为了克服这种应激，细胞机制增加了 Keap1 水平，以下调 Nrf2 的核定位及其依赖的抗氧化系统。在 A549 和 HepG2 细胞中，FA 处理 3 和 6 小时后，抗氧化系统分别达到最低水平。由于内源性 ROS 仍以相同的速度产生，ROS 水平明显高于对照，这将还原性应激转变为氧化性应激。在此条件下暴露于 γ 射线进一步增加了 ROS 水平，并使癌细胞对辐射敏感。与单独辐照（IR）相比，IR 和 FA 的联合处理激活了线粒体凋亡途径，并同时抑制了细胞周期进程和存活途径。此外，与单独放疗相比，联合治疗在肿瘤组织中显示出明显的肿瘤消退、caspase 3 激活和核片段化。相比之下，FA 预处理可保护外周血单核细胞（PBMC）和正常肺成纤维细胞 WI38 免受辐射损伤。总之，联合治疗为杀伤癌细胞提供了有效的策略，并显示出增加放射治疗效果的潜力。
