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The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is

Mark F van Delft1, Andrew H Wei, Kylie D Mason

  • 1The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.

Cancer Cell
|November 14, 2006
PubMed

Insights

The drug ABT-737 effectively triggers apoptosis by targeting Bcl-2 proteins, but resistance occurs when Mcl-1 is present. Inhibiting Mcl-1 can restore sensitivity to ABT-737, improving cancer treatment options.

Area of Science:

  • Molecular biology
  • Cancer research
  • Drug discovery

Background:

  • Malignant cells often overexpress prosurvival B-cell lymphoma 2 (Bcl-2) proteins, impairing apoptosis and leading to chemoresistance.
  • BH3-only proteins are natural antagonists of Bcl-2 family proteins and are crucial regulators of apoptosis.
  • Developing drugs that mimic BH3-only proteins holds promise for overcoming chemoresistance in cancer.

Purpose of the Study:

  • To investigate the efficacy of BH3 mimetics, specifically ABT-737, in triggering apoptosis in cancer cells.
  • To identify the mechanisms underlying resistance to ABT-737.
  • To explore strategies for overcoming ABT-737 resistance.

Main Methods:

  • Testing seven putative BH3 mimetics for their ability to induce apoptosis.
  • Assessing the sensitivity of various cell types to ABT-737.
  • Investigating the role of Mcl-1 in ABT-737 resistance through gene manipulation (downregulation and enforced expression).
  • Utilizing a mouse lymphoma model to study Mcl-1's effect on drug resistance.

Main Results:

  • Only ABT-737 effectively triggered Bax/Bak-mediated apoptosis among the tested BH3 mimetics.
  • ABT-737 demonstrated high affinity for Bcl-2, Bcl-x(L), and Bcl-w, but many cell types were resistant.
  • Resistance to ABT-737 was attributed to its inability to target the prosurvival protein Mcl-1.
  • Downregulating Mcl-1 conferred sensitivity to ABT-737, while enforced Mcl-1 expression led to resistance.
  • Cells overexpressing Bcl-2 remained sensitive to ABT-737.

Conclusions:

  • ABT-737 is a potent BH3 mimetic effective against tumors with low Mcl-1 levels.
  • Mcl-1 is a key determinant of resistance to ABT-737.
  • Combining ABT-737 with agents that inactivate Mcl-1 could overcome resistance, even in Bcl-2 overexpressing tumors.
  • Targeting Mcl-1 represents a viable strategy to enhance the efficacy of ABT-737 in cancer therapy.

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