The Medical Wrld!!!!!

In the life of a cell, the response to DNA damage determines whether the cell is fated to pause and repair itself, commit suicide, or grow uncontrollably, a route leading to cancer. In a new study, published in the July 25th issue of Cell, scientists at NYU Langone Medical Center have identified a way that cells respond to DNA damage through a process that targets proteins for disposal.
The finding points to a new pathway for the development of cancer and suggests a new way of sensitizing cancer cells to treatment.

"One of the major messages of this study is that we have a new pathway that responds to DNA damage," says Michele Pagano, M.D., the May Ellen and Gerald Jay Ritter Professor of Oncology and Professor of Pathology at NYU School of Medicine, who was recently appointed a Howard Hughes Medical Institute Investigator. "It is already known that the three major protein players in this pathway are deregulated in human cancers, so deregulation of this pathway is probably going to contribute to tumorigenesis (the development of cancer)."

DNA damage can be caused by carcinogens in the environment, errors in DNA replication, or glitches in the cellular machinery caused by aging, among other factors. If a cell detects DNA damage when it is about to divide, it activates the so-called G2 checkpoint, a pause button that allows the cell time to correct the problem before cell division, the process whereby a cell makes two copies of itself. The cell maintains a paused state based on a series of proteins, a pathway, that work together like gears in a machine. Some are switched on and others are turned off (often by degradation) to maintain the checkpoint.

In addition to the new pathway's association with cancer, it suggests a potentially new way to sensitize cells to chemotherapy, says Dr. Pagano. Tumor cells already have a less efficient checkpoint because of defects in other regulatory pathways. Up to 60% of cancers, for example, have mutations in p53, a tumor suppressor gene and G2 checkpoint regulator that operates in a separate pathway.

Inhibiting this new pathway with a drug could make cancer cells especially vulnerable to DNA damage, causing cancerous cells to die rather than pausing to correct the problem, Dr. Pagano says. Unlike cancer cells, which already have a less efficient checkpoint, normal cells have a fully functioning G2 checkpoint and divide less frequently, sparing them from drug-induced cell death.

The central player in this pathway is the protein complex called APC/C, which is involved in multiple aspects of cell regulation through a trash disposal system that shreds proteins. In response to DNA damage, the cell targets Cdc14B, an enzyme that rips phosphate groups off of other proteins, to APC/C, an action which turns on the shredder. Once APC/C is turned on, it tags its target, Plk1, for disposal. If Plk1 remains active, the cell will continue to divide. Unlike the G2 checkpoint pathways that have been previously described, the researchers believe this one is "ancient" because it is evolutionarily conserved in organisms from yeast to humans.

According to the study, the deregulation of these three pathway components (Cdc14B, APC/C, and Plk1) in cancer cells correlates with lower survival rates in patients. Researchers will need to perform further studies to determine how these proteins are altered in cancer. Some of the effect might be due to changes in the levels of proteins expressed, but it is currently unknown whether mutations to these proteins might also play a role.

The authors of this study are: Florian Bassermann; Michele Pagano, David Frescas; Daniele Guardavaccaro; Luca Busino and Angelo Peschiaroli. This study was supported by grants from the National Institutes of Health, an Emerald Foundation grant, and fellowships from the German Research Foundation and the America Italian Cancer Foundation.

A new University of Michigan study in mice suggests that a drug recently approved to fight cancer tumors is also able to reduce the effects of graft-versus-host disease, a common and sometimes fatal complication for people who have had bone marrow transplants.
Plans are under way at U-M for an initial trial of the drug in people as a new way to prevent graft-versus-host disease. Researchers expect to begin a trial within a year.

The U-M scientists tested the effects of the drug SAHA, as well as another member of a group of drugs known as HDAC inhibitors, on key immune system cells called dendritic cells. In mice, both drugs were able to significantly diminish the destructive inflammatory effects that these cells cause in graft-versus-host disease.

Graft-versus-host disease occurs when immune cells in the transplanted bone marrow mount a misguided attack on body tissues. If HDAC inhibitors turn out to be safe and effective in people, they might offer a treatment option preferable to the immunosuppressant drugs used now to treat the disease. These leave people vulnerable to infection and have other significant side effects.

"To make bone marrow transplants more effective, we need better control of the very powerful reactions between the immune systems of the donor and recipient. This study shows how drugs like SAHA regulate those reactions, and takes us a major step closer to bringing this new approach to patients who need transplants," says James L.M. Ferrara, M.D., director of the U-M Combined Bone Marrow Transplant Program and a senior author on the study. Ferrara is also professor of internal medicine and pediatric and communicable diseases at U-M.

"These HDAC inhibitors were thought to just kill cancer cells, but at lower doses, it's possible they can modulate a number of immune diseases," says Pavan Reddy, M.D., the study's lead and corresponding author, and an assistant professor of internal medicine at the U-M Medical School. "The mechanism we have identified in graft-versus-host disease may be involved in autoimmune diseases as well."

Context

Bone marrow stem cell transplants are most commonly used to treat leukemia and lymphoma. By replenishing depleted blood cells, the transplants allow higher doses of chemotherapy to more effectively get rid of cancer cells.

But as many as half of bone marrow transplant recipients develop acute or chronic symptoms of graft-versus-host disease, which can affect the skin, liver and gastrointestinal tract. Reddy calls the disease "the single biggest barrier to bone marrow transplant."

The study suggests a novel way to treat graft-versus-host disease with an already available drug that is stirring considerable interest as an anti-cancer agent. The FDA approved SAHA, marketed under the name Vorinostat, as a treatment for one kind of lymphoma in 2006 and for leukemia in 2007. SAHA is being used off label for other cancers, including lung, brain and colon cancer.

The U-M study adds to a growing body of research suggesting HDAC inhibitors also may be useful tools to reign in misguided immune responses. Researchers elsewhere have recently shown that HDAC inhibitors have been beneficial in animal studies of lupus and inflammatory bowel disease. Other studies suggest the drugs could be useful in regulating the immune response in heart and islet cell transplants.

Research details

The U-M researchers studied the responses of immune system dendritic cells in mice given SAHA and ITF 2357, another new HDAC inhibitor. Dendritic cells are important immune system cells whose varied roles are beginning to be fully understood.

The scientists looked at the two HDAC inhibitors' effects on mouse and human dendritic cells in culture. They found that as they suspected, the drugs acted to diminish the dendritic cells' key role in promoting pro-inflammatory proteins called cytokines. Specifically, the researchers found that the HDAC inhibitors increase the expression of IDO, an enzyme which represses dendritic cell activity.

They tested the HDAC inhibitors in mice bred to display the effects of graft -versus-host disease. When they injected the mice with dendritic cells treated with the drugs, they found the drugs were able to reduce the disease's effects.