title: Generation of Redox Imbalance Mediates the Cytotoxic Effect of Malabaricone-A in a Multidrug Resistant Cell Line.
abstract: Multidrug resistance (MDR) refers to cross-resistance to a range of structurally and functionally unrelated compounds, and is accompanied by an elevated expression of ATP driven cell-membrane transporters. The cytotoxicity of Malabaricone-A (MAL-A), a diarylnonanoid derived from Myristica malabarica was demonstrated in leukemic cell lines, but its effectiveness in drug-resistant cancer cell lines has not been evaluated. Accordingly, this study tested its cytotoxic potential in a T-lymphoblastic leukemic cell line, CCRF CEM and its MDR counterpart, CEM/ADR5000. The effectiveness of MAL-A was 1.8 fold higher in CEM/ADR5000 than CCRF CEM cell line, the IC50 being value 5.40 ± 1.41 vs. 9.72 ± 1.08 µg/ml, respectively, suggesting that MAL-A demonstrated 'collateral sensitivity'. This cytotoxicity of MAL-A was attributed to an enhanced generation of oxidative stress, as the IC50 value increased following the addition of an anti-oxidant, N-acetyl cysteine (NAC). Furthermore, MAL-A depleted glutathione and inhibited glutathione peroxidase activity, which too contributed towards generation of a redox imbalance. This culminated in an apoptosis mediated cell death as evident by mitochondrial membrane depolarization, enhanced caspase-3 activity, increased externalization of phosphatidylserine and an increase in the sub G0/G1 population. Collectively, compounds with pro-oxidant activity have promising therapeutic potential in drug resistant phenotypes, worthy of future pharmacological consideration.
authors.forename: Alak
authors.initials: A
authors.lastname: Manna
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Bauri
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Dept. of Pharmacology, Institute of Postgraduate Medical Education and Research, 244 B Acharya JC Bose Road, Kolkata 700 020, India. ilatim@vsnl.net.
authors.forename: Mitali
authors.initials: M
authors.lastname: Chatterjee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D012118:Resorcinols; C522672:malabaricone A