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Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential European Journal of Pharmacology

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential European Journal of Pharmacology
 
Creator Amin, Tanzeeba
Sharma, Rajneesh Paul
Mir, Khalid Bashir
Slathia , Nancy
Chhabra , Sonali
Tsering , Dolma
Kotwal , Pankul
Bhagat, Madhulika
Nandi, Utpal
Parkesh, Raman
Kapoor, Kamal K
Goswami, Anindya
 
Subject QR Microbiology
 
Description AKT and ERK 1/2 play a pivotal role in cancer cell survival, proliferation, migration, and angiogenesis. Therefore, AKT and ERK 1/2 are considered crucial targets for cancer intervention. In this study, we envisaged the role of AKT and ERK signaling in apoptosis regulation in presence of compound 4h, a novel synthetic derivative of quinoxalinone substituted spiropyrrolizines exhibiting substantial antiproliferative activity in various cancer cell lines. Structurally 4h is a spiropyrrolizine derivative. Molecular docking analysis revealed that compound 4h shows strong binding affinity with AKT-1 (-9.5 kcal/mol) and ERK2 (-9.0 kcal/mol) via binding at allosteric sites of AKT and active site of ERK2. The implications of 4h binding with these two survival kinases resulted in the obstruction for ATP binding, hence, hampering their phosphorylation dependent activation. We demonstrate that 4h mediated apoptotic induction via disruption in the mitochondrial membrane potential of MCF-7 and HCT-116 cells and 4h-mediated inhibition of survival pathways occurred in a wild type PTEN background and is diminished in PTEN-/- cells. In 4T1 mammary carcinoma model, 4h exhibited pronounced reduction in the tumor size and tumor volume at significantly low doses. Besides, 4h reached the highest plasma concentration of 5.8 μM within a period of 1 h in mice model intraperitoneally. Furthermore, 4h showed acceptable clearance with an adequate elimination half-life and satisfactory pharmacokinetic behaviour, thus proclaiming as a potential lead molecule against breast and colorectal cancer by specifically inhibiting simultaneously AKT and ERK1/2 kinases.
 
Publisher ELSEVIER
 
Date 2023-10-15
 
Type Article
PeerReviewed
 
Relation https://www.sciencedirect.com/science/article/abs/pii/S0014299923004570?via%3Dihub
http://crdd.osdd.net/open/3160/
 
Identifier Amin, Tanzeeba and Sharma, Rajneesh Paul and Mir, Khalid Bashir and Slathia , Nancy and Chhabra , Sonali and Tsering , Dolma and Kotwal , Pankul and Bhagat, Madhulika and Nandi, Utpal and Parkesh, Raman and Kapoor, Kamal K and Goswami, Anindya (2023) Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential European Journal of Pharmacology. European journal of pharmacology, 957. ISSN 0014-2999