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
| Autor: | Jyotsna Bhat, Supriya Chakraborty, Abhishek Santra, Anup Kumar Misra, Arghya Adhikary, Parimal C. Sen, Subhrangsu Chatterjee, Bhaswati Banerjee, Swatilekha Ghosh |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Indoles Clinical Biochemistry Eukaryotic Initiation Factor-2 Pharmaceutical Science Apoptosis Breast Neoplasms Biology p38 Mitogen-Activated Protein Kinases 03 medical and health sciences Mice 0302 clinical medicine In vivo Cell Line Tumor Animals Humans Cytotoxicity Endoplasmic Reticulum Chaperone BiP Pharmacology Biochemistry (medical) ATF4 Carcinoma Cell Biology Receptor Cross-Talk Activating Transcription Factor 4 Crosstalk (biology) 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Cancer cell Cancer research Unfolded protein response Female Signal transduction Transcription Factor CHOP Signal Transduction |
| Zdroj: | Apoptosis : an international journal on programmed cell death. 21(10) |
| ISSN: | 1573-675X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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