Kuduvalli Shreyas S, Daisy Precilla S, Vaithy Anandraj, Purushothaman Mugilarasi, Ramachandran Muralidharan Arumugam, Agiesh Kumar B, Mezger Markus, Antony Justin S, Subramani Madhu, Dubashi Biswajit, Biswas Indrani, Guruprasad K P, Anitha T S
Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India.
Department of Pathology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India.
Front Pharmacol. 2023 Mar 21;14:1096614. doi: 10.3389/fphar.2023.1096614. eCollection 2023.
Glioma is the most devastating high-grade tumor of the central nervous system, with dismal prognosis. Existing treatment modality does not provide substantial benefit to patients and demands novel strategies. One of the first-line treatments for glioma, temozolomide, provides marginal benefit to glioma patients. Repurposing of existing non-cancer drugs to treat oncology patients is gaining momentum in recent years. In this study, we investigated the therapeutic benefits of combining three repurposed drugs, namely, metformin (anti-diabetic) and epigallocatechin gallate (green tea-derived antioxidant) together with temozolomide in a glioma-induced xenograft rat model. Our triple-drug combination therapy significantly inhibited tumor growth and increased the survival rate (50%) of rats when compared with individual or dual treatments. Molecular and cellular analyses revealed that our triple-drug cocktail treatment inhibited glioma tumor growth in rat model through ROS-mediated inactivation of PI3K/AKT/mTOR pathway, arrest of the cell cycle at G1 phase and induction of molecular mechanisms of caspases-dependent apoptosis.In addition, the docking analysis and quantum mechanics studies performed here hypothesize that the effect of triple-drug combination could have been attributed by their difference in molecular interactions, that maybe due to varying electrostatic potential. Thus, repurposing metformin and epigallocatechin gallate and concurrent administration with temozolomide would serve as a prospective therapy in glioma patients.
神经胶质瘤是中枢神经系统最具破坏性的高级别肿瘤，预后不佳。现有的治疗方式并未给患者带来实质性益处，需要新的治疗策略。神经胶质瘤的一线治疗药物之一替莫唑胺，对神经胶质瘤患者的益处有限。近年来，将现有的非癌症药物重新用于治疗肿瘤患者的做法越来越受到关注。在本研究中，我们在神经胶质瘤诱导的异种移植大鼠模型中，研究了三种重新利用的药物（即二甲双胍（抗糖尿病药物）、表没食子儿没食子酸酯（绿茶衍生的抗氧化剂））与替莫唑胺联合使用的治疗效果。与单独或双重治疗相比，我们的三联药物联合疗法显著抑制了肿瘤生长，并提高了大鼠的存活率（50%）。分子和细胞分析表明，我们的三联药物鸡尾酒疗法通过ROS介导的PI3K/AKT/mTOR通路失活、细胞周期在G1期停滞以及诱导半胱天冬酶依赖性凋亡的分子机制，抑制了大鼠模型中的神经胶质瘤肿瘤生长。此外，此处进行的对接分析和量子力学研究推测，三联药物联合的效果可能归因于它们分子相互作用的差异，这可能是由于静电势的不同。因此，重新利用二甲双胍和表没食子儿没食子酸酯并与替莫唑胺同时给药，将成为神经胶质瘤患者的一种有前景的治疗方法。
