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PAC-1 (first procaspase activating compound) is a synthesized chemical that selectively induces apoptosis, or cell suicide, in cancerous cells. PAC-1 is an extraordinary compound which has a very high likelihood to be introduced into medicine as a better way to cure many cancers. Although this anti-tumor compound has promise and has shown good results in mouse models, many tests are still needed to verify that this chemical is suitable for humans.

PAC-1 Function and Discovery

PAC-1 (pronounced “PACK ONE”) is a chemical that was discovered at the University of Illinois: Urbana-Champaign during a process that screened many chemicals for anti-tumor potential. This molecule, when delivered to cancer cells, signals the cells to self-destruct by activating an “executioner” protein, procaspase-3. Then, the activated executioner protein begins a cascade of events that destroys the machinery of the cell.

Uses of Apoptosis in the Body and its Irregularities

This cascade of events is named apoptosis. Apoptosis is self-induced in cells to combat infections or DNA damage. For instance, when a cell in one’s body is infected with a bacterium or virus, it will self-destruct to take away the resources needed by the virus to proliferate. Apoptosis is also found to help in embryo development (destroying the webbing in between an embryo's fingers to separate the fingers) and the regular replenishment of cells that are constantly being used up or destroyed (cells that line the intestinal tract), also called homeostasis.

A cell undergoing apoptosis. The dying cell blebs apart and sends signals to the phagocytes, which are part of the immune system, to engulf it.

The problem lies when one part of the apoptosis pathway is broken. Normally, the balance between cell division and apoptosis is rigorously regulated to keep the integrity of organs and tissues. Examples of broken apoptosis pathways occur in many cancers today. If old lung cells cannot self-destruct to make room for new lung cells, a large mass of cells form and a tumor is made.

In many cases, the apoptotic pathway is disrupted because procaspase-3, the executioner protein, cannot be activated by the cell. This is analogous an executioner who does not have orders to kill. Without the orders, the condemned will not die. The same analogy can be made with procaspase-3. Without activated procaspase-3, the apoptotic cascade will not occur and the cell will not destroy itself no matter how necessary it may be. PAC-1 acts a replacement order that works and bypasses the lawyers, court orders, and governor's calls. It will activate procaspase-3 indiscriminately.

How PAC-1 Affects the Apoptotic Process

In cells, the executioner protein, caspase-3, is stored in its inactive form, procaspase-3. This way, the cell can quickly undergo apoptosis by activating the protein that is already there. This inactive form is called a zymogen. Procaspase-3 has a “safety catch” made of three aspartate amino acids. When this safety catch is released by the cell, procaspase-3 is activated to caspase-3, which starts the apoptotic cycle. PAC-1 cleaves these three amino acids to activate procaspase-3 into caspase-3. Also, caspase-3 further activates other molecules of procaspase-3 in the cell, causing a exponential increase in caspase-3 concentration. PAC-1 facilitates this process and causes the cell to undergo apoptosis quickly.

Unfortunately, a selectivity problem arises because procaspase-3 is present in most cells of the body. However, it has been shown that in many cancers, including certain neuroblastomas, lymphomas, leukemias, melanomas, and liver cancers, procaspase-3 is actually present in higher concentrations. For instance, lung cancers can have over 1000 times more procaspase-3 than normal cells. Therefore, by controlling the dosage, one can achieve selectivity between normal and cancerous cells.

Further Research and Human Application

Thus far, PAC-1 seems extremely promising as a new anti-tumor drug. It is synthetically available and a few mouse trials have been performed with moderate success. Overall, PAC-1 is the first of many small molecules to directly influence the apoptotic machinery of cells.

External Links

• Cancer cell 'executioner' found. BBC News 27 Aug 2006.

• Cancer cells 'can live forever'. BBC News 29 Apr 2004.

• National Cancer Institute Comprehensive Cancer Information