A series of genes that protect cells from the powerful, common chemotherapeutic agent doxorubicin has been identified by researchers working to understand how the drug also can destroy the heart.
"We found a series of genes that are very important for cell survival in the face of doxorubicin," says Dr. Hernan Flores-Rozas, cancer researcher at the Medical College of Georgia Cancer Center. "At the moment you start inactivating these genes, the cells become very sensitive and don't grow any more. So now we know which genes we need to inactivate in the cell to make it very sensitive to the drug."
Doxorubicin is widely used to treat solid tumors from breast cancer to prostate and ovarian cancer. A slightly modified version, daunorubicin, is a powerful fighter of leukemia and lymphoma and often is used in children.
Unfortunately, just as cancer treatment ends, heart problems can begin for some patients who get these drugs. Heart cells, called cardiomyocytes, can commit suicide, or apoptosis, says Dr. Ling Xia, a graduate student at the Department of Cardiology at China's Wuhan University who is part of an exchange program with MCG. The result is dilative cardiomyopathy, in which the heart becomes a boggy organ that can no longer pump blood out to the body. Damage can even show up years after treatment, she says noting there is no known way to prevent or treat it, short of a heart transplant.
The long-term goal of their research is prevention and maybe enhanced cancer treatment through development of ways to turn these genes off in cancer cells and on in heart cells, says Dr. Flores-Rozas, corresponding author on the study published in the Dec. 1 issue of Cancer Research. Dr. Xia is first author.
Another possibility is turning down their protection in cancer cells, which should necessitate less drug and result in less heart damage, says Dr. Flores-Rozas, noting that it's dose related and cumulative.
They did studies in relatively simple yeast cells from Dr. Anil Cashikar's yeast knockout collection. Yeast, which have about 6,000 genes compared to humans' 30,000, are good models for study of human cells because they include the same basic cellular functions such as replication, DNA repair, signaling and even cell death, says Dr. Cashikar, MCG geneticist and a study co-author.
They found 71 genes that conveyed varying degree of protection from doxorubicin. "The cell does not have a unique mechanism to protect from doxorubicin; it's a very complex response," says Dr. Flores-Rozas. "Some genes protect better than others. But in the absence of some of these genes, the cells will die from exposure to the drug."
The genes may even protect cancer and cardiac cells differently, he says noting one way doxorubicin stops cancer cells is by preventing their classic rapid division. Cardiac cells, on the other hand, don't divide. Still there's some common ground between the cells when it comes to protection. Cardiac cells have been known to use heat shock proteins to protect themselves from toxic injuries. This enables proteins made by cells to continue to function properly. "If you have activated heat shock response, you have more activate proteins," says Dr. Flores-Rozas. "If you have proteins that don't function, the cell is eventually going to die." The MCG researchers have shown the heat shock response also is activated in a stressed cancer cell.
He notes these newly identified protective genes likely already are expressed at some level before the cells are confronted with a stress such as a chemotherapeutic agent, then step up expression in response. "If it doesn't, doxorubicin will kill them," Dr. Flores-Rozas says.
The MCG researchers suspect the genes may be protective from other stresses, such as a viral infection, as well.
They already are looking at their function and expression in cancer and cardiac cells normally and when exposed to doxorubicin.
The research was funded by the National Institutes of Health. Dr. Flores-Rozas is a Georgia Cancer Coalition Distinguished Cancer Scholar.
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