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ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress

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Abstract

Purpose

This study assessed the role of oxidative stress and loss of glutathione in ABT-737-induced apoptosis.

Methods

Jurkat human acute lymphocytic leukemia cells and HeLa cells transfected with a tet-regulated Bcl-2 expression system were treated with ABT-737 or its less active stereoisomer. GSH concentrations, intracellular reactive oxygen species (ROS), caspase activation and apoptotic DNA fragmentation were measured.

Results

ABT-737 induced oxidative stress through decreased GSH and increased intracellular hydrogen peroxide and superoxide levels. Apoptotic DNA fragmentation and caspase activation were the consequences of this oxidative stress. Combining ABT-737 with ROS-inducing agents such as adaphostin or etoposide enhanced cell death.

Conclusions

These results demonstrate that inhibition of Bcl-2 causes a loss of GSH, an increase in ROS, caspase activation and subsequent apoptosis. Clinically, redox alterations as a consequence of Bcl-2 inhibition by ABT-737 should be considered in devising combination therapies with this novel agent or its derivatives.

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Abbreviations

GSH:

Glutathione

ALL:

Acute lymphocytic leukemia

NAC:

N-acetyl cysteine

HE:

Dihydroethidium

H2DCFDA:

Dihydrodichlorofluorescein-diacetate

DCF:

Dichlorofluorescein

OPA:

O-Phthaldialdehyde

PI:

Propidium iodide

ROS:

Reactive oxygen species

CI:

Combination index

CFTR:

Cystic fibrosis transmembrane conductance regulator

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Acknowledgments

This work was supported in part by RO1 CA69003 to R.M. and RO1 CA115811 to J.C.

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Authors and Affiliations

  1. Department of Pediatrics Research, The University of Texas M. D. Anderson Cancer Center, Box 853, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Adrienne N. Howard & Joya Chandra

  2. Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

    Kathleen A. Bridges & Raymond E. Meyn

Authors
  1. Adrienne N. Howard
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  2. Kathleen A. Bridges
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  3. Raymond E. Meyn
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  4. Joya Chandra
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Correspondence to Joya Chandra.

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Howard, A.N., Bridges, K.A., Meyn, R.E. et al. ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress. Cancer Chemother Pharmacol 65, 41–54 (2009). https://doi.org/10.1007/s00280-009-1001-1

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  • DOI: https://doi.org/10.1007/s00280-009-1001-1

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