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Mephebrindole, a synthetic indole analog coordinates the crosstalk between p38MAPK and eIF2α/ATF4/CHOP signalling pathways for induction of apoptosis in human breast carcinoma cells

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Abstract

The efficacy of cancer chemotherapeutics is limited by side effects resulting from narrow therapeutic windows between the anticancer activity of a drug and its cytotoxicity. Thus identification of small molecules that can selectively target cancer cells has gained major interest. Cancer cells under stress utilize the Unfolded protein response (UPR) as an effective cell adaptation mechanism. The purpose of the UPR is to balance the ER folding environment and calcium homeostasis under stress. If ER stress is prolonged, tumor cells undergo apoptosis. In the present study we demonstrated an 3,3′-(Arylmethylene)-bis-1H-indole (AMBI) derivative 3,3′-[(4-Methoxyphenyl) methylene]-bis-(5-bromo-1H-indole), named as Mephebrindole (MPB) as an effective anti-cancer agent in breast cancer cells. MPB disrupted calcium homeostasis in MCF7 cells which triggered ER stress development. Detailed evaluations revealed that mephebrindole by activating p38MAPK also regulated GRP78 and eIF2α/ATF4 downstream to promote apoptosis. Studies extended to in vivo allograft mice models revalidated its anti-carcinogenic property thus highlighting the role of MPB as an improved chemotherapeutic option.

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Abbreviations

MPB:

Mephebrindole

UPR:

Unfolded protein response

ER stress:

Endoplasmic reticulum stress

GRP78:

Glucose regulated protein 78

ATF4:

Activating transcription factor 4

CHOP:

CCAAT-enhancer-binding protein homologous protein

eIF2α:

Eukaryotic initiation factor 2α

ChIP:

Chromatin immunoprecipitation

p38 MAPK:

p38 Mitogen activated protein kinase

AMBI:

Aryl methyl bis-indolyl derivative

NAC:

N-Acetyl cysteine

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Acknowledgments

We are thankful to Prof. Tamara Lah and Dr. Neža Podergajs, National Institute of Biology, Ljubljana, Slovenia for kindly gifting us the MCF 10A cell line. Thanks are due to A. Basu, R. Dutta and K. Das for technical help. This work was supported by the grants from Department of Atomic Energy, Gov’t of India. Authors acknowledge Bose Institute and The Center for Research in Nanoscience and Nanotechnology, University of Calcutta, for providing some instrumental facilities. SC thanks DBT for the RGYI Grant BT/PR6627/GBD/27/440/2012.

Authors contributions

SC, SG, BB, and PCS conceived the study and designed the experiments. SC, SG, BB, AS, JB performed the experiments. SC, AA, SC, AKM analyzed the data and prepared the figures. SC and SG wrote the paper. PCS supervised the study and revised the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India

    Supriya Chakraborty, Swatilekha Ghosh, Bhaswati Banerjee, Abhishek Santra, Anup K. Misra & Parimal C. Sen

  2. Department of Biophysics, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India

    Jyotsna Bhat & Subhrangsu Chatterjee

  3. Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India

    Arghya Adhikary

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  1. Supriya Chakraborty
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  2. Swatilekha Ghosh
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  9. Parimal C. Sen
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Correspondence to Parimal C. Sen.

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Chakraborty, S., Ghosh, S., Banerjee, B. et al. Mephebrindole, a synthetic indole analog coordinates the crosstalk between p38MAPK and eIF2α/ATF4/CHOP signalling pathways for induction of apoptosis in human breast carcinoma cells. Apoptosis 21, 1106–1124 (2016). https://doi.org/10.1007/s10495-016-1268-8

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