Generation of Redox Imbalance Mediates the Cytotoxic Effect of Malabaricone-A in a Multidrug Resistant Cell Line
Ajay K Bauri,
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.
Keywords: Apoptosis, drug resistance, malabaricone-A, oxidative stress, pro-oxidant.
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