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Drug Insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms

Nature Clinical Practice Oncology volume 3, pages 388–398 (2006)Cite this article

Abstract

Cell death is a normal facet of human physiology, ensuring tissue homeostasis by offsetting cell production with cell demise. Neoplasms arise in part because of defects in physiological cell death mechanisms, contributing to pathological cell expansion. Defects in normal cell death pathways also contribute to cancer progression by permitting progressively aberrant cell behaviors, while also desensitizing tumor cells to immune-mediated attack, radiation, and chemotherapy. Through basic research, much has been learned about the molecular mechanisms responsible for cell turnover and how tumors escape cell death. By exploiting this knowledge base, several innovative strategies for eradicating malignancies have materialized that are based on restoration of natural pathways for cell autodestruction. Some of these strategies have advanced into human clinical trials. Several of the current strategies based on targeting core components of the cell death machinery for cancer therapy are reviewed here, and a summary of progress toward clinical applications is provided.

Key Points

  • Drugs that restore apoptosis sensitivity to cancer cells are promising candidates for a new generation of anticancer therapy

  • Antiapoptotic Bcl-2-family proteins block a mitochondrial pathway for cell death that is largely responsible for the cytotoxic activity of conventional anticancer drugs

  • Clinical trials of a DNA-based drug targeting Bcl-2 show evidence of bioactivity against several types of chemorefractory cancer

  • TRAIL is a cytokine that selectively induces apoptosis of cancer cells, often bypassing roadblocks to apoptosis found in chemorefractory tumors

  • Agonistic antibodies that bind and activate TRAIL receptors appear to be safe in humans, and represent one of the possibilities for activating the same apoptosis pathway that is often employed by immune cells for attacking tumors

  • IAP-family proteins block distal steps in apoptosis pathways; compounds that neutralize IAPs show promising preclinical activity, and DNA-based drugs targeting IAPs are undergoing testing in early-stage human clinical trials

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Figure 1: Schematic diagram representing the interplay between different caspase proteins and cell death regulatory proteins involved in regulating apoptosis, autophagy and necrosis.

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Authors and Affiliations

  1. President and Chief Executive Officer of Burnham Institute for Medical Research, La Jolla, CA, USA

    John C Reed

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JC Reed is the inventor of Genasense and is entitled to receive royalty payments if drug sales are initiated.

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Reed, J. Drug Insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Rev Clin Oncol 3, 388–398 (2006). https://doi.org/10.1038/ncponc0538

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