August 27, 2006
Drug Triggers Suicide In Cancer Cells

Many types of cancer cells have a surplus of procaspase-3. Procaspase-3 can be converted to caspase-3 which initiates the cell suicide process called apoptosis. However, cancer cells have mutations which prevent the conversion of procaspase-3 to caspase-3. Well, a team of scientists developed a drug called procaspase activating compound one (PAC-1) which converts procaspase-3 to caspase-3 and thereby initiates cell suicide.

CHAMPAIGN, Ill. -- Scientists have found a way to trick cancer cells into committing suicide. The novel technique potentially offers an effective method of providing personalized anti-cancer therapy. Most living cells contain a protein called procaspase-3, which, when activated, changes into the executioner enzyme caspase-3 and initiates programmed cell death, called apoptosis. In cancer cells, however, the signaling pathway to procaspase-3 is broken. As a result, cancer cells escape destruction and grow into tumors.

"We have identified a small, synthetic compound that directly activates procaspase-3 and induces apoptosis," said Paul J. Hergenrother, a professor of chemistry at the University of Illinois at Urbana-Champaign and corresponding author of a paper to be posted online this week ahead of regular publication by the journal Nature Chemical Biology. "By bypassing the broken pathway, we can use the cells' own machinery to destroy themselves."

To find the compound, called procaspase activating compound one (PAC-1), Hergenrother, with colleagues at the U. of I., Seoul National University, and the National Center for Toxicological Research, screened more than 20,000 structurally diverse compounds for the ability to change procaspase-3 into caspase-3.

Cancer cells are more susceptible to the drug because they have more procaspase-3.

The treatment works because procaspase-3 is often much more abundant in cancer cells than in healthy cells, says Paul Hergenrother at University of Illinois in Urbana, US, who led the study: “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.”

Tumor cells were enormously more sensitive to the PAC-1 drug as compared to non-cancer cells.

Healthy cells, such as white blood cells, were found to be significantly less affected by the addition of PAC-1 because they had much lower levels of procaspase-3, so cell-suicide could not be triggered.

When the scientists tested PAC-1 on cancerous and non-cancerous tissue from the same person, the tumour cells were 2,000-fold more sensitive to PAC-1.

But not all cancer types have elevated levels of procaspase-3 to serve as a drug target.

"It is now clear that many cancers have elevated concentrations of procaspase-3," wrote Prof Hergenrother in the Nature paper. "Others have heightened or reduced concentrations of procaspase-3 depending on the cancer subtype." He added that a systematic analysis of procaspase-3 concentrations in a variety of cancer types was needed to determine which cancers would be most amenable to treatment with a molecule such as PAC-1.

The continued discovery of differences between cancerous and normal cells will provide more targets for anti-cancer drug development. The continued advance in general understanding of cell metabolism and gene regulation will lead to the discovery of many more enzymes and intra-cellular messengers which will become targets for anti-cancer drug development.

I am very optimistic that most of us will live long enough to witness the total defeat of cancer.

Share |      Randall Parker, 2006 August 27 10:31 PM  Biotech Cancer

Alexandre Finkel said at August 31, 2006 3:47 PM:

It is fantastic!

As a person diagnosted with the prostate cancer I can hardly wait to know if PAC-1 drug

can treat the prostate cancer.

Please, let me know, where the paper by professor Paul J. Hergenrother will be posted online.

Thank you!

Not My Second Opinion said at September 3, 2006 3:42 AM:

I am not quite so optimistic because of research budget constraints and stem cell research limitations that have been put on by the Bush administration... but I digress.

Here's the abstract and citation for the upcoming article via PubMed:

Nat Chem Biol. 2006 Aug 27; [Epub ahead of print]
Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy.

* Putt KS,
* Chen GW,
* Pearson JM,
* Sandhorst JS,
* Hoagland MS,
* Kwon JT,
* Hwang SK,
* Jin H,
* Churchwell MI,
* Cho MH,
* Doerge DR,
* Helferich WG,
* Hergenrother PJ.

Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.

Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, concentrations of procaspase-3 in certain cancerous cells are significantly higher than those in noncancerous controls. Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. We found that PAC-1 retarded the growth of tumors in three different mouse models of cancer, including two models in which PAC-1 was administered orally. PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3, a transformation that allows induction of apoptosis even in cells that have defective apoptotic machinery. The direct activation of executioner caspases is an anticancer strategy that may prove beneficial in treating the many cancers in which procaspase-3 concentrations are elevated.

PMID: 16936720 [PubMed - as supplied by publisher]

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