Apoptosis, or programmed cell death, is a major mechanism to keep cells toeing the line of their parent organism. But if cells give up too easily, chaos will ensue; or at the very least, lots of energy will end up going to replacing cells that still were quite serviceable.
For that reason, cells have evolved complex regulatory mechanisms that includes something of a last-chance mechanism: the inhibitors of apoptosis proteins, or IAPs, which "put the brakes on apoptotic proteins," probably to prevent accidental cell death, Wayne Fairbrother, director of protein engineering at Genentech Inc., told BioWorld Today. And because they are overexpressed in cancer cells, drug discovery efforts have been directed toward IAPs for some time now.
Among the critical interactions of IAPs is their relationship with Smac protein. In normal cells, Smac is found only in mitochondria, and so it binds to IAPs - which are in the cytoplasm - only after mitochondria have been damaged. When Smac binds to IAPs, the IAPs are no longer able to inhibit the activation of caspases, which leads to cell death.
A number of papers have demonstrated that Smac mimetics can be used in combination with other agents to inhibit IAPs and restore apoptosis.
This week, no fewer than three papers - one in Cancer Cell and two in Cell - reported that IAP antagonists can restore apoptosis on their own under certain circumstances, as well as the molecular details of how apoptosis is restored when IAPs are inhibited.
The details of the methodologies vary, but Fairbrother, who is co-author of one of the Cell papers, noted that "all three papers demonstrate that IAP antagonists lead to TNF-dependent apoptosis in sensitive cell lines."
That single-agent activity, he added, was "initially a surprise," because the classical understanding of IAPs is that they block apoptosis in response to pro-apoptotic signaling. Removing the block would allow pro-apoptotic signals to pass through, but not create them by itself.
The reason it does, the researchers found, is that when Smac mimetics bind to IAPs, those IAPs are marked for degradation by the proteasome. Smac mimetics also enable the activation of NF-kappaB, which in turn leads to the production of TNF-alpha. And TNF-alpha is a pro-apoptotic signaling molecule that provides the necessary push toward suicide.
Not all cell lines produce TNF-alpha in response to Smac mimetics, but in the Cancer Cell paper, researchers tested 50 human non-small-cell lung cancer cell lines in culture and found that almost a quarter of them were sensitive to Smac mimetics. Some breast and melanoma cell lines also were sensitive to Smac mimetics as single agents.
The Cancer Cell paper appears in the November 2007 issue and is titled "Autocrine TNFalpha Signaling Renders Human Cancer Cells Susceptible to Smac-Mimetic-Induced Apoptosis." Its authors are from University of Texas Southwestern Medical Center and Joyant Pharmaceuticals, both in Dallas.
Both Cell papers appear in the Nov. 16, 2007, issue. The first Cell paper is titled "IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-kappaB Activation, and TNFalpha-Dependent Apoptosis," and published by researchers from South San Francisco-based Genentech.
The second paper, which includes researchers from Latrobe University in Melbourne, Australia, as well as other academic collaborators and industrial collaborators from TetraLogic Pharmaceuticals, of Malvern, Pa, 3-02B, of Singapore, and Ozgene Pty Ltd., of Perth, Australia, is titled "IAP Antagonists Target cIAP1 to Induce TNFalpha-Dependent Apoptosis."
Genentech is in Phase I trials with an IAP antagonist, though Fairbrother said it is not the same one used in the experiments described in Cell.