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28 Aug, (foodconsumer.org) - A synthetic molecule that triggers cancer cells to commit suicide was effective in mouse cancer models, scientists said. They hope the finding will herald in new drugs that can activate this mechanism that causes cancer cells to hasten their own death.

The molecule killed human lung cancer cells and kidney cancer cells in mouse models and may give rise to drugs that can potentially activate the "executioner" mechanism in human cancer cells, the researchers said. The compound called procaspase activating compound, or PAC-1 transforms into caspase-3, which is a terminator enzyme that kills the cancer cells.

Normally the vast numbers of cells in the human body are active for a fixed number of days. When their activity nears its end internal mechanisms activate enzymes that destroy the cells. This physiological process is called apoptosis. However in cancer cells, this mechanism is shut off allowing the cancer to grow unhindered.

Chemically procaspase-3 is activated when normal cell death is imminent. In cancer although procaspase-3 levels are high, there is no activation mechanism and hence apoptosis cannot take place.

Chemist Paul Hergenrother of the University of Illinois and an international team of colleagues theorized that a compound that could activate procaspase-3 may induce cancer cells to kill themselves. The researchers screened 20,500 related molecules for this activation ability, but were able to find five molecules that could induce the process of programmed cell death in cancer.

Among these five compounds, they found that only one showed an increasingly strong effect with increased doses and that compound was named procaspase activating compound, or PAC-1.

"We have identified a small, synthetic compound that directly activates procaspase-3 and induces apoptosis," Hergenrother said. "By bypassing the broken pathway, we can use the cells' own machinery to destroy them." In order to test the efficacy of this compound, researchers induced human cancers in mouse models.

The testing was performed in collaboration with William Helferich, a professor of food science and human nutrition at the U. of I., and Myung-Haing Cho at Seoul National University. Colon cancer cells obtained from patients at a local hospital were used to observe the action of PAC-1.

The cancer cells had elevated levels of procaspase-3, which were roughly eight times as that found in normal colon cells. Researchers found that the cancer cells were very sensitive to PAC-1. “In tissue from 23 colon cancer patients we found that, on average, levels of procaspase-3 are eightfold higher than in healthy cells – sometimes as much as 20-fold higher," Hergenrother said.

In one instance cancer cells were 2,000 times more sensitive to PAC-1 and underwent apoptosis at a rapid rate. The surrounding healthy cells remained unaffected since the cancer cells expressed huge amounts of procaspase-3.

"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 said in the report, which appears in the online edition of the journal Nature Chemical Biology.

The researchers then tested the compound in mice that had human lung cancer and kidney cancer. These cancers contain about five times more procaspase-3 than healthy cells. The researchers treated the mice for two months with the compound.

“In the lung cancer experiments, the control mice ended up riddled with tumors, but in the treated lungs there was hardly any sign of the tumors,” Hergenrother told New Scientist. In two months of treatment, the tumors were greatly reduced in mice, which received the compound, while the cancer spread in control mice.

The treatment worked even when the compound was given orally and scientists said that it might be effective when given in the form of pills. Hergenrother said that in future cancer patients could be screened before the compound was administered.

Patients with cancers, which express large amounts of procaspase-3 levels, would be eligible, he said. “It means you’d have the executioner ready and waiting for activation in cancer cells,” Hergenrother added. “And the more procaspase-3 there is relative to healthy cells, the more sensitive the cancer cells are to PAC-1, so the less you’d have to give the patient to kick-start action.”

Hergenrother further pointed out that calling caspase-3 as an “executioner” protein makes sense since this activation is the final step before cell death. The idea is that once the protein is activated, its action cannot be stopped at all. This method is preferable to the one, which seeks to trigger apoptosis by repairing damaged signals like p-53 protein, which is apoptosis gene.

“We’ve found a compound that can bypass the entire cascade, so you don’t need to worry if there’s any damaged machinery above caspase-3,” said Hergenrother.

However before clinical trials can begin toxicity and dose data need to be studied more extensively. Currently, the Illinois group is working on more efficient doses of PAC-1. Hergenrother said their initial targets were lung and colon cancers.

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