Trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic PI3K/Akt/mTOR signaling pathway

Chakrabhavi Dhananjaya Mohan, V. Srinivasa, Shobith Rangappa, Lewis Mervin, Surender Mohan, Shardul Paricharak, Sefer Baday, Feng Li, Muthu K. Shanmugam, Arunachalam Chinnathambi, M. E. Zayed, Sulaiman Ali Alharbi, Andreas Bender, Gautam Sethi, Basappa, Kanchugarakoppal S. Rangappa

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

Abstract

Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.

Original languageEnglish
Article numbere0153155
JournalPLoS ONE
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 2016

Bibliographical note

Publisher Copyright:
© 2016 Mohan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted se, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding

This research was supported by University Grants Commission (41-257-2012-SR), Vision Group Science and Technology, Department of Science and Technology (NO. SR/FT/LS-142/2012) to Basappa. KSR thanks Department of Science and Technology Indo-Korea [INT/Indo-Korea/122/2011-12] and Institution of Excellence, University of Mysore for financial support and instrumentation facility. CDM thanks the University of Mysore for Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE) Research Associate fellowship. This work was supported by NUHS Bench-to-Bedside-To-Product grant to GS. Deanship of Scientific Research, College of Science Research Centre, King Saud University, Kingdom of Saudi Arabia is also acknowledged. SP thanks the Netherlands Organisation for Scientific Research (NWO, grant number NWO-017.009–065) and the Prins Bernhard Cultuurfonds for funding.

FundersFunder number
DST-PURSE
Department of Science and Technology Indo-KoreaINT/Indo-Korea/122/2011-12
Prins Bernhard Cultuurfonds
University of Mysore for Department of Science and Technology-Promotion of University Research and Scientific Excellence
Department of Science and Technology, Ministry of Science and Technology, IndiaSR/FT/LS-142/2012
University Grants Commission41-257-2012-SR
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO-017.009–065
National University Health System
University of Mysore

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