title: Induction of intrinsic and extrinsic apoptosis through oxidative stress in drug-resistant cancer by a newly synthesized Schiff base copper chelate.
abstract: Multidrug resistance (MDR) in cancer represents a variety of strategies employed by tumor cells to evade the beneficial cytotoxic effects of structurally different anticancer drugs and thus confers impediments to the successful treatment of cancers. Efflux of drugs by MDR protein-1, functional P-glycoprotein and elevated level of reduced glutathione confer resistance to cell death or apoptosis and thus provide a possible therapeutic target for overcoming MDR in cancer. Previously, we reported that a Schiff base ligand, potassium-N-(2-hydroxy 3-methoxy-benzaldehyde)-alaninate (PHMBA) overcomes MDR in both in vivo and in vitro by targeting intrinsic apoptotic/necrotic pathway through induction of reactive oxygen species (ROS). The present study describes the synthesis and spectroscopic characterization of a copper chelate of Schiff base, viz., copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate (CuPHMBA) and the underlying mechanism of cell death induced by CuPHMBA in vitro. CuPHMBA kills both the drug-resistant and sensitive cell types irrespective of their drug resistance phenotype. The cell death induced by CuPHMBA follows apoptotic pathway and moreover, the cell death is associated with intrinsic mitochondrial and extrinsic receptor-mediated pathways. Oxidative stress plays a pivotal role in the process as proved by the fact that antioxidant enzyme; polyethylene glycol conjugated-catalase completely blocked CuPHMBA-induced ROS generation and abrogated cell death. To summarize, the present work provides a compelling rationale for the future clinical use of CuPHMBA, a redox active copper chelate in the treatment of cancer patients, irrespective of their drug-resistance status.
authors.affiliation: a Department of In Vitro Carcinogenesis and Cellular Chemotherapy , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Kaushik
authors.initials: K
authors.lastname: Banerjee
authors.affiliation: a Department of In Vitro Carcinogenesis and Cellular Chemotherapy , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Soumya
authors.initials: S
authors.lastname: Basu
authors.affiliation: a Department of In Vitro Carcinogenesis and Cellular Chemotherapy , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Satyajit
authors.initials: S
authors.lastname: Das
authors.affiliation: a Department of In Vitro Carcinogenesis and Cellular Chemotherapy , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Abhinaba
authors.initials: A
authors.lastname: Sinha
authors.affiliation: b Department of Chemistry , Ramakrishna Mission Residential College , Kolkata , West Bengal , India.
authors.forename: Manas Kumar
authors.initials: MK
authors.lastname: Biswas
authors.affiliation: a Department of In Vitro Carcinogenesis and Cellular Chemotherapy , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Soumitra Kumar
authors.initials: SK
authors.lastname: Choudhuri
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001547:Benzaldehydes / Q000737:chemistry; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D056831:Coordination Complexes / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D011092:Polyethylene Glycols / Q000737:chemistry; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D012545:Schiff Bases / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001547:Benzaldehydes; D002614:Chelating Agents; D056831:Coordination Complexes; D017382:Reactive Oxygen Species; D012545:Schiff Bases; D011092:Polyethylene Glycols; D003300:Copper; D002374:Catalase; D000409:Alanine
keywords: Apoptosis; cancer multidrug resistance; copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate; mitochondria; reactive oxygen species