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Assessment of Cytotoxic Effects of New Derivatives of Pyrazino[1,2-A] Benzimidazole on Isolated Human Glioblastoma Cells and Mitochondria Publisher Pubmed



Rahimifard M1 ; Haghiaminjan H2 ; Hadjighassem M3, 4 ; Pourahmad Jaktaji R5 ; Bagheri Z6 ; Azami Movahed M7 ; Zarghi A7 ; Pourahmad J8
Authors
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Authors Affiliations
  1. 1. Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  2. 2. Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
  3. 3. Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Genetics, Faculty of Sciences, Shahrekord University, Shahrekord, Iran
  6. 6. Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C, Tehran, Iran
  7. 7. Department of Medicinal and Pharmaceutical Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  8. 8. Faculty of Pharmacy, Department of Pharmacology/Toxicology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Source: Life Sciences Published:2021


Abstract

Aims: Glioblastoma multiforme (GBM) is a highly devastating malignant brain tumor with poor pharmacotherapy. Based on COX-2 inhibitory effects in preventing cancer progression, new pyrazino[1,2-a]benzimidazole derivatives were assessed on isolated human GBM cells. Main methods: In this study, firstly, primary culture of astrocytes from human GBM samples was prepared and exposed to 2,6-dimethyl pyrazino[1,2-a]benzimidazole (L1) and 3,4,5-trimethoxy pyrazino[1,2-a]benzimidazole (L2) for finding their half-maximal inhibitory concentration (IC50). In the following, in two phases, cell apoptosis pathway and mitochondrial markers were investigated on GBM and also HEK293 cells (as non-cancerous normal cells). Key findings: The MTT results represented a remarkable selective cytotoxic effect of both L1 and L2 on GBM cells, and interestingly not on normal cells. After 48 h, IC50 of L1 and L2 were calculated as 13 μM and 85 μM, respectively. Annexin/PI staining showed that L1 and L2 induce apoptosis in GBM cells, and caspase measurement showed that apoptosis occurs through mitochondrial signaling. In the clonogenic assay, GBM cells formed more paraclones and fewer holoclones after treating with L1 and L2. L1 and L2 also selectively enhanced mitochondrial damaged markers, including reactive oxygen species (ROS) formation, and mitochondrial swelling, decreased mitochondrial membrane potential (MMP) and cytochrome c release in isolated cancerous GBM mitochondria. Significance: Our findings on human primary astrocyte cells illustrated that L1 and L2 compounds, with COX-2 inhibitory effect, through the intrinsic pathway of apoptosis concerning mitochondrial damage enhancement have therapeutic potentials on GBM. © 2021