Antiproliferative and apoptotic effects of indole derivative, N-(2-hydroxy-5-nitrophenyl (4'-methylphenyl) methyl) indoline in breast cancer cells.

Abstract

Indoline derivatives functions as an inhibitors of epidermal growth factor receptor (EGFR) with the anticancer potential against various cancers. We aim to investigate anti-breast cancer effects and mechanism of action of novel indoline derivatives. Molecular docking of seven indoline derivates with EGFR revealed, N-(2-hydroxy-5-nitrophenyl (4'-methylphenyl) methyl) indoline (HNPMI) as the top lead compound. RT-PCR analysis showed the downregulation of PI3K/S6K1 genes in breast cancer cells through the activation of EGFR with HNPMI. This compound found to have higher cytotoxicity than Cyclophosphamide, with the IC50 of 64.10 μM in MCF-7 and 119.99 μM in SkBr3 cells. HNPMI significantly reduced the cell proliferation of MCF-7 and SkBr3 cells, without affecting non-cancerous cells, H9C2. Induction of apoptosis was analyzed by Caspase-3 and -9, DNA fragmentation, AO/EtBr staining and flow cytometry assays. A fold change of 0.218- and 0.098- for caspase-3 and 0.478- and 0.269- for caspase-9 in MCF7 and SkBr3 cells was observed, respectively. Caspase mediated apoptosis caused DNA fragmentation in breast cancer cells upon HNPMI treatment. The structural elucidation of HNPMI by QSAR model and ADME-Tox suggests, a bi-molecular interaction of HNPMI-EGFR which is related to antiproliferative and apoptotic activity. The data concludes that, HNPMI-induced the apoptosis via EGFR signaling pathway in breast cancer cells. Thus, HNPMI might serve as a scaffold for developing a potential anti-breast cancer therapeutic agent.

• Authors: Suresh Palanivel, Akshaya Murugesan, Kumar Subramanian, Olli Yli-Harja, Meenakshisundaram Kandhavelu
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 881 Pg. 173195 (Aug 15 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32446710 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Indoles
• N-(2-hydroxy-5-nitrophenyl (4'-methylphenyl) methyl) indoline
• Phosphatidylinositol 3-Kinase
• EGFR protein, human
• ErbB Receptors
• Ribosomal Protein S6 Kinases, 70-kDa
• ribosomal protein S6 kinase, 70kD, polypeptide 1
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9

Topics

• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Proliferation (drug effects)
• ErbB Receptors (antagonists & inhibitors, chemistry, metabolism)
• Female
• Humans
• Indoles (chemistry, pharmacokinetics, pharmacology)
• MCF-7 Cells
• Molecular Docking Simulation
• Phosphatidylinositol 3-Kinase (metabolism)
• Protein Conformation
• Quantitative Structure-Activity Relationship
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction