Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran; Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran; Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
Eur J Pharmacol. 2018 Feb 5;820:274-285. doi: 10.1016/j.ejphar.2017.12.041. Epub 2017 Dec 20.
Glioblastoma multiform (GBM) accounts for the most common form of primary brain tumors with very limited survival rate. Drug resistance is the main challenges for good prognosis of GBM patients. Arsenic trioxide (ATO) as a multifunctional drug has been investigated for the treatment of several solid tumors. Amplification/overexpression of the epidermal growth factor receptor (EGFR) gene as a signature genetic abnormality of GBM tumors can be a chemoresistance mechanism. In this study, we use erlotinib as an EGFR inhibitor to increase the sensitivity of GBM cell lines to ATO treatment. We evaluate the effects of this combination on metabolic activity, viability, cell proliferation, colony formation, cell cycle distribution, migration, oxidative stress and reactive oxygen species production. Our results showed that combination of ATO with erlotinib synergistically reduced metabolic activity, proliferation and colony forming potential in treated GBM cell lines. This combination induced G2/M cell cycle arrest. We also found that wound-healing rate were suppressed only after combination treatment. In addition, apoptotic cell death and reactive oxygen species content significantly increased after combination treatment. The combination of ATO and erlotinib considerably interfere with survival and migration of treated GBM cell lines through cell cycle arrest and reactive oxygen species production. Present study uncovered that EGFR inhibition could overcome the resistance of glioblastoma cells to ATO treatment.
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，其生存率非常有限。药物耐药性是影响 GBM 患者预后的主要挑战。三氧化二砷（ATO）作为一种多功能药物，已被用于治疗多种实体肿瘤。表皮生长因子受体（EGFR）基因的扩增/过表达是 GBM 肿瘤的标志性遗传异常，可能是一种化疗耐药机制。在本研究中，我们使用厄洛替尼作为 EGFR 抑制剂来提高 GBM 细胞系对 ATO 治疗的敏感性。我们评估了这种联合用药对代谢活性、活力、细胞增殖、集落形成、细胞周期分布、迁移、氧化应激和活性氧产生的影响。我们的结果表明，ATO 与厄洛替尼联合使用可协同降低治疗的 GBM 细胞系的代谢活性、增殖和集落形成能力。这种联合用药诱导了 G2/M 细胞周期阻滞。我们还发现，只有在联合治疗后，划痕愈合率才受到抑制。此外，细胞凋亡和活性氧含量在联合治疗后显著增加。ATO 和厄洛替尼的联合用药通过细胞周期阻滞和活性氧产生，严重干扰了治疗的 GBM 细胞系的存活和迁移。本研究揭示了 EGFR 抑制可以克服胶质母细胞瘤细胞对 ATO 治疗的耐药性。
