title: Modulation of cell death in human colorectal and breast cancer cells through a manganese chelate by involving GSH with intracellular p53 status.
abstract: Chemotherapy is central to current treatment modality especially for advanced and metastatic colorectal and breast cancers. Targeting the key molecular events of the neoplastic cells may open a possibility to treat cancer. Although some improvements in understanding of colorectal and breast cancer treatment have been recorded, the involvement of glutathione (GSH) and dependency of p53 status on the modulation of GSH-mediated treatment efficacy have been largely overlooked. Herein, we tried to decipher the underlying mechanism of the action of Mn-N-(2-hydroxyacetophenone) glycinate (MnNG) against differential p53 status bearing Hct116, MCF-7, and MDA-MB-468 cells on the backdrop of intracellular GSH level and reveal the role of p53 status in modulating GSH-dependant abrogation of MnNG-induced apoptosis in these cancer cells. Present study discloses that MnNG targets specifically wild-type-p53 expressing Hct116 and MCF-7 cells by significantly depleting both cytosolic, mitochondrial GSH, and modulating nuclear GSH through Glutathione reductase and Glutamate-cysteine ligase depletion that may in turn induce p53-mediated intrinsic apoptosis in them. Thus GSH addition abrogates p53-mediated apoptosis in wild-type-p53 expressing cells. GSH addition also overrides MnNG-induced modulation of phase II detoxifying parameters in them. However, GSH addition partially replenishes the down-regulated or modulated GSH pool in cytosol, mitochondria, and nucleus, and relatively abrogates MnNG-induced intrinsic apoptosis in p53-mutated MDA-MB-468 cells. On the contrary, although MnNG induces significant cell death in p53-null Hct116 cells, GSH addition fails to negate MnNG-induced cell death. Thus p53 status with intracellular GSH is critical for the modulation of MnNG-induced apoptosis.
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700 026, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Banerjee
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700 026, India.
authors.forename: Satyajit
authors.initials: S
authors.lastname: Das
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Majumder
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Subrata
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700 026, India.
authors.forename: Jaydip
authors.initials: J
authors.lastname: Biswas
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700 026, India. soumitra01@yahoo.com.
authors.forename: Soumitra Kumar
authors.initials: SK
authors.lastname: Choudhuri
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
chemical_list: D002614:Chelating Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008345:Manganese; D005978:Glutathione; D005998:Glycine
keywords: Apoptosis; Colorectal and breast cancer; Glutathione; Phase II detoxifying enzymes; Schiff-based manganese complex; p53