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Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy

Ryuji Yamaguchi1, Edith Janssen, Guy Perkins

  • 1Program of Cell Death and Apoptosis, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America. rudy.yamaguchi@gmail.com

Plos One
|September 28, 2011
PubMed

Insights

Combining Bcl-2 inhibitors (ABT) with 2-deoxyglucose (2DG) enhances apoptosis in resistant cancer cells. This novel strategy effectively targets tumors, offering a potential alternative to traditional genotoxic therapies.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Cell Death Pathways

Background:

  • Bcl-2 family antagonists (ABT) induce apoptosis in limited cell types due to resistance mechanisms.
  • 2-deoxyglucose (2DG) inhibits glycolysis, slowing tumor growth with minimal toxicity to normal tissues.

Purpose of the Study:

  • To investigate the synergistic effect of combining ABT and 2DG on apoptosis induction in ABT-resistant cancer cells.
  • To elucidate the molecular mechanisms underlying the enhanced apoptotic response.
  • To evaluate the efficacy of this combination therapy against chemo-resistant prostate cancer xenografts.

Main Methods:

  • Pre-treatment of cancer cells with 2DG followed by ABT.
  • Assessment of apoptosis via cytochrome c release and caspase activation.
  • Analysis of Bak/Bax and Mcl-1/Bcl-xL protein interactions.
  • In vivo efficacy studies using human prostate cancer xenografts in mice.

Main Results:

  • 2DG pre-treatment sensitized ABT-resistant cells to ABT-induced apoptosis at submicromolar concentrations.
  • The combination treatment promoted Bak/Bax-dependent cytochrome c release and caspase activation.
  • 2DG was found to interfere with Bak-Mcl-1 association, facilitating Bak release and subsequent apoptosis.
  • Combination therapy demonstrated significant efficacy against metastatic, chemo-resistant prostate cancer xenografts.

Conclusions:

  • Combining 2DG with ABT represents a potent strategy to overcome Bcl-2 inhibitor resistance.
  • The mechanism involves 2DG priming cells by disrupting Mcl-1 interactions, enhancing ABT-mediated apoptosis.
  • This combination therapy shows promise as a safe and effective alternative to genotoxic cancer treatments.

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