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Suicide is the regular mode of cell death. When cells reach the end of their useful life, internal mechanisms kick in and the cell automatically perishes, a process known as apoptosis. But in cancer cells this mechanism has often been genetically disabled or otherwise broken, allowing tumors to proliferate. Now researchers have found a way to reactivate programmed cell death and thereby treat cancer.
In preparation for apoptosis, a chain of chemical events takes place in the cell. Near the end, the chemical procaspase-3 is activated. This chemical then transforms into caspase-3--an executioner enzyme that terminates the cell. Chemist Paul Hergenrother of the University of Illinois and an international team of colleagues realized that a compound that activated procaspase-3 might be effective in killing cancer, because many tumors show elevated levels of procaspase despite their inability to complete apoptosis. After screening 20,500 related molecules for this activation ability, the researchers narrowed it down to four likely candidates. Of these, only one showed an increasingly strong effect with increased doses: newly named procaspase activating compound, or PAC-1. "We have identified a small, synthetic compound that directly activates procaspase-3 and induces apoptosis," Hergenrother says. "By bypassing the broken pathway, we can use the cells' own machinery to destroy them."
The researchers tested the efficacy of PAC-1 on colon cancer cells (pictured above) from 23 patients. The tumors had elevated levels of procaspase-3 averaging roughly eight times as much as normal colon cells and proved more sensitive to the compound. In one case, the cancerous cells were 2,000 times more sensitive to PAC-1's enforced apoptosis than were surrounding regular cells due to their increased expression of the enzyme. Further tests in mice proved effective in treating grafted human kidney- and lung-cancer cells, and those results also indicated that PAC-1's strength correlated with procaspase-3 levels in the various cancer cells. "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," Hergenrother adds. Nature Chemical Biology published the paper presenting the finding online yesterday.
