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: Alak Manna, Ajay K Bauri, Subrata Chattopadhyay, Mitali Chatterjee
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 15 Issue 9 Pg. 1156-63 ( 2015) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 26032963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Reactive Oxygen Species
• Resorcinols
• malabaricone A

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Drug Synergism
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Oxidation-Reduction
• Reactive Oxygen Species (metabolism)
• Resorcinols (pharmacology)