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PLoS By Category | Recent PLoS Articles
Biochemistry - Pharmacology

Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line
Published: Thursday, May 10, 2012
Author: Alak Manna et al.

by Alak Manna, Piu Saha, Avijit Sarkar, Debanjan Mukhopadhyay, Ajay K. Bauri, Deepak Kumar, Padma Das, Subrata Chattopadhyay, Mitali Chatterjee

Background

The ‘two-faced’ character of reactive oxygen species (ROS) plays an important role in cancer biology by acting both as secondary messengers in intracellular signaling cascades and sustaining the oncogenic phenotype of cancer cells, while on the other hand, it triggers an oxidative assault that causes a redox imbalance translating into an apoptotic cell death.

Principal Findings

Using a tetrazolium [{3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl}-2H-tetrazolium] based cell viability assay, we evaluated the cytotoxicity of a plant derived diarylnonanoid, malabaricone-A on leukemic cell lines U937 and MOLT-3. This cytotoxicity hinged on its ability to cause a redox imbalance via its ability to increase ROS, measured by flow cytometry using 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and by decreasing glutathione peroxidase activity. This redox imbalance mediated apoptosis was evident by an increase in cytosolic [Ca2+], externalization of phosphatidyl serine as also depolarization of the mitochondrial membrane potential as measured by flow cytometry. There was concomitant peroxidation of cardiolipin, release of free cytochrome c to cytosol along with activation of caspases 9, 8 and 3. This led to cleavage of the DNA repair enzyme, poly (ADP-ribose) polymerase that caused DNA damage as proved by labeling with 4',6-diamidino-2-phenylindole (DAPI); furthermore, terminal deoxy ribonucleotide transferase catalysed incorporation of deoxy uridine triphosphate confirmed DNA nicking and was accompanied by arrest of cell cycle progression.

Conclusions

Taken together, compounds like MAL-A having pro-oxidant activity mediate their cytotoxicity in leukemic cells via induction of oxidative stress triggering a caspase dependent apoptosis.

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