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A combination of 2-deoxy-d-glucose and 6-aminonicotinamide induces oxidative stress mediated selective radiosensitization of malignant cells via mitochondrial dysfunction

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Tumor Biology

Abstract

Oxidative stress-mediated mitochondrial dysfunction is known to induce intrinsic pathway of apoptosis. Previously, we have shown that a combination of metabolic modifiers 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) results in oxidative stress-mediated radiosensitization of malignant cells via noncoordinated expression of antioxidant defense. We now show that the combination (2-DG + 6-AN + 2Gy) induces significant alterations in mitochondrial membrane potential and oxidative damage to lipid and proteins selectively in malignant cells resulting in the release of cytochrome c from mitochondria and increase in Bax/Bcl-2 ratio stimulating intrinsic pathway of apoptosis, besides enhancing the mitotic death linked to cytogenetic damage. These results highlight the role of mitochondrial dysfunction in selective radiosensitization by 2-DG + 6-AN, besides inhibition of energy-linked DNA repair processes and generation of oxidative stress reported earlier.

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Abbreviations

2-DG:

2-Deoxy-d-glucose

6-AN:

6-Aminonicotinamide

ROS:

Reactive oxygen species

PBS:

Phosphate-buffered saline

PI:

Propidium iodide

Δψm:

Mitochondrial membrane potential

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazole-carbocyanine iodide

DHE:

Dihydroethidium

NAO:

10-N-nonyl acridine orange

FCCP:

Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone

FITC:

Fluorescein isothiocyanate

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Acknowledgement

We are thankful to Dr. R P Tripathi, Director, Institute of Nuclear Medicine and Allied Sciences for his support. We thank Dr. N. Raghuram, Associate Prof. School of Biotechnology, Guru Gobind Singh Indraprastha University, Delhi for his technical comments. We also thank Mrs. Namita kalra for her help in flowcytometry experiments. Mr. Pradeep Kumar Sharma is a recipient of ICMR fellowship.

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Authors and Affiliations

  1. Institute of Nuclear Medicine and Allied Sciences, DRDO, Brig S K Mazumdar Road, Delhi, 110 054, India

    Richa Bhardwaj, Pradeep Kumar Sharma & Rajeev Varshney

  2. Department of Chemistry, Shri Varshneya College, Aligarh, UP, India

    Suryaprakash Singh Jadon

  3. School of Biotechnology, Guru Gobind Singh Indraprastha University, Dwarka, New Delhi, 110 075, India

    Pradeep Kumar Sharma

  4. Ministry of Defence, Government of India, 533, O/o SA to RM, Secretary Defence R&D & DG DRDO, DRDO Bhawan, Rajaji Marg, New Delhi, 110 105, India

    Rajeev Varshney

Authors
  1. Richa Bhardwaj
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  2. Pradeep Kumar Sharma
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  3. Suryaprakash Singh Jadon
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  4. Rajeev Varshney
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Corresponding author

Correspondence to Rajeev Varshney.

Additional information

Richa Bhardwaj and Pradeep Kumar Sharma contributed equally to this work.

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Bhardwaj, R., Sharma, P.K., Jadon, S.S. et al. A combination of 2-deoxy-d-glucose and 6-aminonicotinamide induces oxidative stress mediated selective radiosensitization of malignant cells via mitochondrial dysfunction. Tumor Biol. 32, 951–964 (2011). https://doi.org/10.1007/s13277-011-0197-y

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