Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC, 29209, USA.
Apoptosis. 2020 Apr;25(3-4):217-232. doi: 10.1007/s10495-020-01590-9.
Glioblastoma is the most malignant and prevalent brain tumor in adults. It can grow and spread quickly causing harm to the brain health. One of the major challenges in treatment of glioblastoma is drug resistance. Use of synergistic combination of two drugs with different anti-tumor effects is nowadays highly considered in the development of effective therapeutic strategies for many malignancies. In the present study, we showed synergistic therapeutic efficacies of two chemical compounds, N-(4-hydroxyphenyl) retinamide (4HPR) and suberoylanilide hydroxamic acid (SAHA), for significant reduction in cell viability of rat C6 and human T98G glioblastoma cells. These compounds (4HPR and SAHA) were used alone or in synergistic combination for evaluating their various anti-tumor effects. The results showed that combination of 4HPR and SAHA significantly induced morphological and molecular features of astrocytic differentiation in C6 and T98G glioblastoma cells. Combination of 4HPR and SAHA proved to be an important therapeutic strategy for inhibiting cell growth and inducing differentiation in glioblastoma cells. Furthermore, combination of the two drugs showed more efficacies than either dug alone in reducing in vitro cell invasion (transwell assay), cell migration (wound healing assay), and angiogenesis (tube formation assay) due to down regulation of the molecules involved in these processes. The ultimate of goal of using this combination of drugs was induction of apoptosis. The results showed that these drugs in synergistic combination contributed highly to increases in morphological and molecular features of apoptotic death in the tumor cells. The results from molecular studies indicated that cell death occurred via activation of the extrinsic and intrinsic pathways of apoptosis in both C6 and T98G cells. The drugs in combination also contributed to dramatic inhibition of histone deacetylase 1, an important epigenetic player in promoting growth in glioblastoma cells. This novel combination of drugs should also be considered as a promising therapeutic strategy for the treatment of glioblastoma in vivo.
胶质母细胞瘤是成年人中最恶性和最常见的脑肿瘤。它可以快速生长和扩散，对大脑健康造成伤害。治疗胶质母细胞瘤的主要挑战之一是耐药性。现在，在许多恶性肿瘤的有效治疗策略的开发中，非常考虑使用两种具有不同抗肿瘤作用的药物的协同组合。在本研究中，我们显示了两种化学化合物 N-（4-羟基苯基）视黄酰胺（4HPR）和琥珀酰亚胺基羟肟酸（SAHA）的协同治疗功效，可显着降低大鼠 C6 和人 T98G 神经胶质瘤细胞的细胞活力。这些化合物（4HPR 和 SAHA）单独或联合使用，以评估其各种抗肿瘤作用。结果表明，4HPR 和 SAHA 的组合显着诱导 C6 和 T98G 神经胶质瘤细胞的星形胶质细胞分化的形态和分子特征。4HPR 和 SAHA 的组合被证明是抑制神经胶质瘤细胞生长和诱导分化的重要治疗策略。此外，由于涉及这些过程的分子下调，两种药物的组合在减少体外细胞侵袭（Transwell 测定），细胞迁移（伤口愈合测定）和血管生成（管形成测定）方面比单独使用任何一种药物都更有效。使用这种药物组合的最终目标是诱导细胞凋亡。结果表明，这些药物在协同组合中高度有助于增加肿瘤细胞凋亡死亡的形态和分子特征。分子研究结果表明，细胞死亡通过激活两种 C6 和 T98G 细胞中外源和内在凋亡途径发生。组合药物还极大地抑制了组蛋白去乙酰化酶 1，这是促进神经胶质瘤细胞生长的重要表观遗传因子。这种药物联合也应被视为治疗体内胶质母细胞瘤的有前途的治疗策略。
