Synthetic Molecule Causes Cancer Cells to Commit Suicide

Investigators have found a way to trick cancer cells into self-destructing. The unique method could possibly provide an effective way to provide customized anti-cancer therapy.

Most living cells contain a protein called procaspase-3, which, when activated, transforms into the executioner enzyme caspase-3 and initiates programmed cell death, called apoptosis. In cancer cells, however, the signaling pathway to procaspase-3 is disrupted. As a result, cancer cells evade destruction and grow into tumors.

"We have identified a small, synthetic compound that directly activates procaspase-3 and induces apoptosis,” said Dr. Paul J. Hergenrother, a professor of chemistry at the University of Illinois at Urbana-Champaign (UIUC; USA) and corresponding author of an article posted online in August 2006 in the journal Nature Chemical Biology. "By bypassing the broken pathway, we can use the cells' own machinery to destroy themselves.”

To identify the compound, called procaspase-activating compound 1(PAC-1), Dr. Hergenrother, with colleagues at the UIUC, Seoul National University (Cambodia), and the U.S. National Center for Toxicological Research (Jefferson, AR, USA), screened more than 20,000 structurally diverse compounds for the ability to convert procaspase-3 into caspase-3. The researchers assessed the compound's efficacy in cell cultures and in three mouse models of cancer. The researchers also were able to demonstrate that PAC-1 killed cancer cells in 23 tumors obtained from a local hospital.

Cell death was correlated with the level of procaspase-3 present in the cells, with more procaspase-3 resulting in cell death at lower concentrations of PAC-1. "This is the first in what could be a host of organic compounds with the ability to directly activate executioner enzymes,” said Dr. Hergenrother, who is also an affiliate of the Institute for Genomic Biology at UIUC. "The potential effectiveness of compounds such as PAC-1 could be predicted in advance, and patients could be selected for treatment based on the amount of procaspase-3 found in their tumor cells.”

Such customized drug strategies are preferred over therapies that rely on traditional cytotoxins, according to the investigators, and could be the future of anti-cancer therapy.



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