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

doi:10.1371/journal.pone.0153155

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

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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 language	English
Article number	e0153155
Journal	PLoS ONE
Volume	11
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0153155
Publication status	Published - 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.

Funders	Funder number
DST-PURSE
Department of Science and Technology Indo-Korea	INT/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, India	SR/FT/LS-142/2012
University Grants Commission	41-257-2012-SR
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	NWO-017.009–065
National University Health System
University of Mysore

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Mohan, C. D., Srinivasa, V., Rangappa, S., Mervin, L., Mohan, S., Paricharak, S., Baday, S., Li, F., Shanmugam, M. K., Chinnathambi, A., Zayed, M. E., Alharbi, S. A., Bender, A., Sethi, G., Basappa, & Rangappa, K. S. (2016). Trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic PI3K/Akt/mTOR signaling pathway. PLoS ONE, 11(4), Article e0153155. https://doi.org/10.1371/journal.pone.0153155

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

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. Na{\"i}ve 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.",

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

note = "Publisher Copyright: {\textcopyright} 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.",

year = "2016",

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Mohan, CD, Srinivasa, V, Rangappa, S, Mervin, L, Mohan, S, Paricharak, S, Baday, S, Li, F, Shanmugam, MK, Chinnathambi, A, Zayed, ME, Alharbi, SA, Bender, A, Sethi, G, Basappa & Rangappa, KS 2016, 'Trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic PI3K/Akt/mTOR signaling pathway', PLoS ONE, vol. 11, no. 4, e0153155. https://doi.org/10.1371/journal.pone.0153155

TY - JOUR

T1 - Trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic PI3K/Akt/mTOR signaling pathway

AU - Mohan, Chakrabhavi Dhananjaya

AU - Srinivasa, V.

AU - Rangappa, Shobith

AU - Mervin, Lewis

AU - Mohan, Surender

AU - Paricharak, Shardul

AU - Baday, Sefer

AU - Li, Feng

AU - Shanmugam, Muthu K.

AU - Chinnathambi, Arunachalam

AU - Zayed, M. E.

AU - Alharbi, Sulaiman Ali

AU - Bender, Andreas

AU - Sethi, Gautam

AU - Basappa,

AU - Rangappa, Kanchugarakoppal S.

N1 - 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.

PY - 2016/4

Y1 - 2016/4

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0153155

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AN - SCOPUS:84978045141

SN - 1932-6203

VL - 11

JO - PLoS ONE

JF - PLoS ONE

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ER -

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

Abstract

Bibliographical note

Funding

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