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Anticancer Drugs

Partnering to promote apoptosis

Nature Reviews Drug Discovery volume 7, page 805 (2008)Cite this article

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In the first study, Kung and colleagues investigated whether resistance to the receptor tyrosine kinase inhibitor imatinib could be overcome by targeting inhibitor of apoptosis proteins (IAPs), which can block the activity of caspases that are the final effectors of apoptosis. Although a small-molecule IAP inhibitor, LBW242, had no activity in glioma cells on its own, combination with imatinib, which inhibits platelet-derived growth factor receptor (PDGFR), increased sensitization to the apoptotic effects of imatinib.

The authors then established how the synergistic induction of apoptosis is achieved. It was found that imatinib activates the intrinsic apoptosis pathway and mitochondrial outer membrane permeabilization, but caspase 3 and caspase 7 are not activated unless IAPs are simultaneously blocked with LBW242. This occurred independently of the status of the anti-apoptotic AKT pathway. When the authors determined the effect of imatinib on pro- and anti-apoptotic mediators, imatinib resulted in a reduction in the expression of NOL3, which encodes the anti-apoptotic protein ARC. NOL3 expression was associated with glioma progression in patients, and in glioma cells, increased expression of NOL3 led to decreased apoptosis.

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ORIGINAL RESEARCH PAPERS

  1. Ziegler, D. S. et al. Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins. J. Clin. Invest. 118, 3109–3122 (2008)

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  2. Frew, A. J. et al. Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist. Proc. Natl Acad. Sci. USA 105, 11317–11322 (2008)

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Authors
  1. Charlotte Harrison
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Harrison, C. Partnering to promote apoptosis. Nat Rev Drug Discov 7, 805 (2008). https://doi.org/10.1038/nrd2687

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