title: 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.
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.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
authors.forename: Supriya
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
authors.forename: Swatilekha
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Banerjee
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Santra
authors.affiliation: Department of Biophysics, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Bhat
authors.affiliation: Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India.
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: Department of Biophysics, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
authors.forename: Subhrangsu
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
authors.forename: Anup K
authors.initials: AK
authors.lastname: Misra
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India. parimal@jcbose.ac.in.
authors.forename: Parimal C
authors.initials: PC
authors.lastname: Sen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D020239:Receptor Cross-Talk / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D007211:Indoles; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C030374:indole; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Breast cancer; Calcium; ER stress; Reactive oxygen species; Unfolded protein response; p38MAPK