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- Title
The SMAC mimetic AT-101 exhibits anti-tumor and antimetastasis activity in lung adenocarcinoma cells by the IAPs/caspase-dependent apoptosis and p65-NFκB cross-talk.
- Authors
Ahmad, Irfan; Irfan, Safia; Beg, Mirza Masroor Ali; Kamli, Hossam; Ali, Syed Parveen; Begum, Naseem; Alshahrani, Mohammad Y.; Rajagopalan, Prasanna
- Abstract
Objective(s): The Inhibitors of Apoptosis (IAPs) regulate initiator and effector phases of caspase mediated apoptosis. This study evaluates the effects of SMAC mimetic AT-101 in regulation of IAPs/caspases/NFκB-p65 in an adenocarcinoma cell line. Materials and Methods: MTT assay was performed in the NCI-H522 cell line. Flow cytometry was used for detecting cell cycle, apoptosis, and NFκB-p65 regulation. Effects of AT-101 on IAPs and caspases were determined by quantitative real time-PCR and western blotting. AutoDock-VINA was used for computational analysis. Results: AT-101 reduced the cell proliferation of NCI-H522 with a GI50 value of 7 µM. The compound arrested adenocarcinoma cells in the G1 phase of the cell cycle and increased early and late phase apoptosis while decreasing tumor-cell trans-migration. AT-101 treatment to NCI H522 at a concentration of 0.35 µM decreased XIAP, cIAP-1, and cIAP-2 mRNA levels to 4.39±0.66, 1.93±0.26, and 2.20±0.24 folds, respectively. Increased dose of AT-101 at 0.7 µM concentration further decreased XIAP, cIAP-1, and cIAP-2 mRNA levels to 2.44±0.67, 1.46±0.93, and 0.97±0.10 folds, respectively. Similar effects of a dose-dependent decrease in the protein expressions of XIAP, cIAP-1, and cIAP-2 were observed with AT-101 treatments, while a dose-responsive increase in the mRNA and protein expression levels of caspase 6 and caspase 7 was observed in the NCI-H522 cell line. The compound exhibited binding affinity (-6.1 kcal/mol) and inhibited NFκB-p65 in these cells. Conclusion: AT-101 had anti-tumor efficacy against lung adenocarcinoma cells which could be mediated through IAPs/caspase-dependent apoptosis and NFκB-p65 cross talk. Results from this study suggests a signal cross talk between IAPs and NFkB and open new channels for further investigations in therapeutic intervention against lung cancer management.
- Subjects
APOPTOSIS; CELL cycle; CASPASES; ADENOCARCINOMA; LUNGS; ERLOTINIB
- Publication
Iranian Journal of Basic Medical Sciences, 2021, Vol 24, Issue 7, p969
- ISSN
2008-3866
- Publication type
Article
- DOI
10.22038/ijbms.2021.56400.12586