The SMAC mimetic AT-۱۰۱ exhibits anti-tumor and anti-metastasis activity in lung adenocarcinoma cells by the IAPs/ caspase-dependent apoptosis and p۶۵-NFƙB cross-talk

Irfan Ahmad; Safia Irfan; Mirza Masroor Ali Beg; Hosam Kamli; Syed Parveen Ali; Naseem Begum; . Mohammad Alshahrani; Prasanna Rajagopalan

The SMAC mimetic AT-۱۰۱ exhibits anti-tumor and anti-metastasis activity in lung adenocarcinoma cells by the IAPs/ caspase-dependent apoptosis and p۶۵-NFƙB cross-talk

محل انتشار: مجله علوم پایه پزشکی ایران، دوره: 24، شماره: 7

سال انتشار: 1400

نوع سند: مقاله ژورنالی

زبان: انگلیسی

مشاهده: 218

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لینک ثابت به این مقاله:

https://civilica.com/doc/1252797

شناسه ملی سند علمی:

JR_IJBMS-24-7_014

تاریخ نمایه سازی: 19 مرداد 1400

چکیده مقاله:

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-۱۰۱ in regulation of IAPs/caspases/NFƙB-p۶۵ in an adenocarcinoma cell line.Materials and Methods: MTT assay was performed in the NCI-H۵۲۲ cell line. Flow cytometry was used for detecting cell cycle, apoptosis, and NFƙB-p۶۵ regulation. Effects of AT-۱۰۱ on IAPs and caspases were determined by quantitative real time-PCR and western blotting. AutoDock-VINA was used for computational analysis. Results: AT-۱۰۱ reduced the cell proliferation of NCI-H۵۲۲ with a GI۵۰ value of ۷ μM. The compound arrested adenocarcinoma cells in the G۱ phase of the cell cycle and increased early and late phase apoptosis while decreasing tumor-cell trans-migration. AT-۱۰۱ treatment to NCI H۵۲۲ at a concentration of ۰.۳۵ μM decreased XIAP, cIAP-۱, and cIAP-۲ mRNA levels to ۴.۳۹±۰.۶۶, ۱.۹۳±۰.۲۶, and ۲.۲۰±۰.۲۴ folds, respectively. Increased dose of AT-۱۰۱ at ۰.۷ μM concentration further decreased XIAP, cIAP-۱, and cIAP-۲ mRNA levels to ۲.۴۴±۰.۶۷, ۱.۴۶±۰.۹۳, and ۰.۹۷±۰.۱۰ folds, respectively. Similar effects of a dose-dependent decrease in the protein expressions of XIAP, cIAP-۱, and cIAP-۲ were observed with AT-۱۰۱ treatments, while a dose-responsive increase in the mRNA and protein expression levels of caspase ۶ and caspase ۷ was observed in the NCI-H۵۲۲ cell line. The compound exhibited binding affinity (-۶.۱ kcal/mol) and inhibited NFƙB-p۶۵ in these cells. Conclusion: AT-۱۰۱ had anti-tumor efficacy against lung adenocarcinoma cells which could be mediated through IAPs/caspase-dependent apoptosis and NFƙB-p۶۵ 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.

کلیدواژه ها:

AT-۱۰۱ ، Caspases ، IAPs ، NCI-H۵۲۲ ، NFƙB ، SMAC mimetic

نویسندگان

Irfan Ahmad