Department of Biological Sciences, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan 333031, India.
Department of Pharmacy, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan 333031, India.
Oncol Rep. 2018 Jun;39(6):2787-2796. doi: 10.3892/or.2018.6373. Epub 2018 Apr 16.
Glioblastoma multiforme (GBM), often referred to as a grade IV astrocytoma, is the most invasive type of tumor arising from glial cells. The main treatment options for GBM include surgery, radiation and chemotherapy. However, these treatments tend to be only palliative rather than curative. Poor prognosis of GBM is due to its marked resistance to standard therapy. Currently, temozolomide (TMZ), an alkylating agent is used for treatment of GBM. However, GBM cells can repair TMZ‑induced DNA damage and therefore diminish the therapeutic efficacy of TMZ. The potential to evade apoptosis by GBM cells accentuates the need to target the non‑apoptotic pathway and/or inhibition of pro‑survival strategies that contribute to its high resistance to conventional therapies. In recent studies, it has been demonstrated that HDAC inhibitors, such as vorinostat (suberoyl anilide hydroxamic acid; SAHA) can induce autophagy in cancer cells, thereby stimulating autophagosome formation. In addition, a lysosomotropic agent such as chloroquine (CQ) can result in hyper‑accumulation of autophagic vacuoles by inhibiting autophagosome‑lysosome fusion, which can drive the cell towards apoptosis. Hence, we postulated that combination treatment with SAHA and CQ may lead to increased formation of autophagosomes, resulting in its hyper‑accumulation and ultimately inducing cell death in GBM cells. In the present study, we demonstrated that CQ co‑treatment enhanced SAHA‑mediated GBM cell apoptosis. Inhibition of the early stage of autophagy by 3‑methyladenine pre‑treatment reduced cell death confirming that apoptosis induced by CQ and SAHA was dependent on autophagosome accumulation. We also demonstrated that autophagy inhibition led to enhanced ROS, mitochondria accumulation and reduced mitochondrial membrane potential resulting in cell death. The present study provides cellular and molecular evidence concerning the combined effect of SAHA and CQ which can be developed as a therapeutic strategy for the treatment of glioblastoma in the future.
多形性胶质母细胞瘤（GBM），通常被称为 4 级星形细胞瘤，是源自神经胶质细胞的最具侵袭性的肿瘤类型。GBM 的主要治疗选择包括手术、放疗和化疗。然而，这些治疗方法往往只是姑息性的，而不是治愈性的。GBM 预后不良的原因是其对标准治疗具有明显的耐药性。目前，替莫唑胺（TMZ），一种烷化剂，用于治疗 GBM。然而，GBM 细胞可以修复 TMZ 诱导的 DNA 损伤，从而降低 TMZ 的治疗效果。GBM 细胞逃避细胞凋亡的潜力强调了需要靶向非凋亡途径和/或抑制有助于其对传统疗法高度耐药的生存策略。在最近的研究中，已经证明 HDAC 抑制剂，如伏立诺他（琥珀酰亚胺羟肟酸；SAHA）可以在癌细胞中诱导自噬，从而刺激自噬体的形成。此外，溶酶体趋化剂如氯喹（CQ）可以通过抑制自噬体-溶酶体融合导致自噬泡的过度积累，从而促使细胞走向凋亡。因此，我们假设 SAHA 和 CQ 的联合治疗可能会导致自噬体的形成增加，导致其过度积累，并最终诱导 GBM 细胞死亡。在本研究中，我们证明了 CQ 共同处理增强了 SAHA 介导的 GBM 细胞凋亡。3-甲基腺嘌呤预处理抑制自噬的早期阶段减少了细胞死亡，证实了 CQ 和 SAHA 诱导的细胞凋亡依赖于自噬体的积累。我们还证明了自噬抑制导致 ROS、线粒体积累增加和线粒体膜电位降低，导致细胞死亡。本研究提供了关于 SAHA 和 CQ 联合作用的细胞和分子证据，这可以作为未来治疗胶质母细胞瘤的一种治疗策略。
