Sending a Cell-Death Sentence

Science's STKE  07 Sep 2004:
Vol. 2004, Issue 249, pp. tw319
DOI: 10.1126/stke.2492004tw319

Cancer cells proliferate because they evade programmed cell death pathways, and much effort is being devoted to find ways to activate apoptotic pathways in such cells (see the Perspective by Denicourt and Dowdy). Key interactions that determine whether cells live or die are mediated by so-called BH3 (BCL-2 homology 3) domains, which are found in proteins that regulate apoptosis. Such signals can be mimicked or disrupted by peptides that resemble the interaction domains, but such molecules have major shortcomings as experimental or therapeutic agents because of low potency, instability, and inefficient delivery to cells. Walensky et al. now show that these problems could be overcome when a BH3 domain that promotes apoptosis was held in its native α-helical form by a chemical modification they call a hydrocarbon staple. The modified peptide showed increased binding affinity for its target, was relatively protease resistant, and could cross cell membranes. Preliminary studies in animals even showed that the modified peptides could decrease growth of transplanted tumors in mice. The activity of caspases, the cysteine proteases that mediate cell death by apoptosis, is held in check by inhibitor of apoptosis proteins (IAPs). The protein known as Smac promotes apoptosis by binding to IAPs and relieving inhibition of caspases. Li et al. show that the effect of the Smac peptide can be potently mimicked by a small membrane-permeable molecule. Studies with the compound revealed that the well-known requirement for inhibition of protein synthesis to allow apoptotic effects of tumor necrosis factor-α (TNF-α) likely reflects decreased IAP-mediated inhibition of caspases. The new compound sensitized cancer cells in culture to TNF-α-induced cell death.

L. D. Walensky, A. L. Kung, I. Escher, T. J. Malia, S. Barbuto, R. Wright, G. Wagner, G. L. Verdine, S. J. Korsmeyer, Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305, 1466-1470 (2004). [Abstract] [Full Text]

L. Li, R. M. Thomas, H. Suzuki, J. K. De Brabander, X. Wang, P. G. Harran, A small molecule Smac mimic potentiates TRAIL- and TNFα-mediated cell death. Science 305, 1471-1474 (2004). [Abstract] [Full Text]

C. Denicourt, S. F. Dowdy, Targeting apoptotic pathways in cancer cells. Science 305, 1411-1413 (2004). [Summary] [Full Text]