Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400085, India.
Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400085, India.
Biochim Biophys Acta Gen Subj. 2019 May;1863(5):857-869. doi: 10.1016/j.bbagen.2019.02.010. Epub 2019 Feb 20.
Nanoparticle-based therapies have emerged as a promising approach to overcome limitations of conventional chemotherapy. Present study investigates the potential of oleic acid-functionalized iron-oxide nanoparticles (MN-OA) to enhance the radiation response of fibrosarcoma tumor and elucidates its underlying mechanism.
Various cellular and molecular assays (e.g. MTT, clonogenic, cell cycle analysis, cell death, DNA damage/repair) and tumor growth kinetics were employed to investigate the mechanism of MN-OA induced radio-sensitization.
Mouse (WEHI-164) and human (HT-1080) fibrosarcoma cells treated with MN-OA and gamma-radiation (2 Gy) showed a significant decrease in the cell proliferation. Combination treatment showed significant decrease in clonogenic survival of WEHI-164 cells and was found to induce cell cycle arrest, apoptosis and mitotic catastrophe. The mechanism of radio-sensitization was found to involve binding of MN-OA with HSP90, resulting in down-regulation of its client proteins, involved in cell cycle progression (Cyclin B1 and CDC2) and DNA-double strand break repair (e.g. RAD51 and BRCA1). Consistently, longer persistence of DNA damage in cells treated with MN-OA and radiation was observed in the form of γ-H2AX foci. The efficacy and mechanism of MN-OA-induced radio-sensitization was also validated in an immuno-competent murine fibrosarcoma model.
This study reveals the key role of HSP90 in the mechanism of tumor radio-sensitization by MN-OA.
Present work provides a deeper understanding about the mechanism of MN-OA-induced tumor radiosensitization, highlighting the role of HSP90 protein. In addition to diagnostic and magnetic hyperthermia abilities, present remarkable radiosensitizing activity of MN-OA would further excite the clinicians to test its anti-cancer potential.
基于纳米粒子的治疗方法已经成为克服传统化疗局限性的一种有前途的方法。本研究探讨了油酸功能化氧化铁纳米粒子（MN-OA）增强纤维肉瘤肿瘤放射反应的潜力，并阐明了其潜在机制。
采用各种细胞和分子测定（如 MTT、集落形成、细胞周期分析、细胞死亡、DNA 损伤/修复）和肿瘤生长动力学研究 MN-OA 诱导放射增敏的机制。
用 MN-OA 和 γ 射线（2Gy）处理的小鼠（WEHI-164）和人（HT-1080）纤维肉瘤细胞显示细胞增殖明显减少。联合治疗显著降低了 WEHI-164 细胞的集落形成存活率，并发现诱导细胞周期停滞、凋亡和有丝分裂灾难。放射增敏的机制被发现涉及 MN-OA 与 HSP90 结合，导致其客户蛋白下调，参与细胞周期进程（细胞周期蛋白 B1 和 CDC2）和 DNA 双链断裂修复（如 RAD51 和 BRCA1）。一致地，在用 MN-OA 和辐射处理的细胞中观察到更长时间的 DNA 损伤以 γ-H2AX 焦点的形式存在。在免疫功能正常的鼠纤维肉瘤模型中也验证了 MN-OA 诱导的放射增敏的功效和机制。
本研究揭示了 HSP90 在 MN-OA 诱导肿瘤放射增敏机制中的关键作用。
本工作提供了对 MN-OA 诱导肿瘤放射增敏机制的更深入了解，强调了 HSP90 蛋白的作用。除了诊断和磁热疗能力外，MN-OA 目前显著的放射增敏活性将进一步激发临床医生测试其抗癌潜力。
