Miller School Researchers Publish Findings On Kaposi's Sarcoma

Main Category: HIV / AIDS
Article Date: 07 May 2009 - 0:00 PDT

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New findings just published in the Proceedings of the National Academy of Sciences (PNAS) by University of Miami Miller School of Medicine researchers suggest that antioxidant therapy could help prevent and treat Kaposi's sarcoma, a major AIDS-related malignancy. Even though the number of cases has gone down with the use of highly active antiretroviral therapy, Kaposi's sarcoma still has a high death rate, particularly in Sub-Saharan Africa.

Recently it has been found that the human herpesvirus 8 (HHV8) is responsible for the development of Kaposi's hallmark skin and mucosal lesions, making it a class of tumors induced by a viral infection. While the human herpesvirus 8 causes the disease, the molecular mechanisms responsible for the tumors have remained an enigma.

Scientists at the University of Miami Miller School of Medicine's Sylvester Comprehensive Cancer Center and other collaborating universities have been able to reproduce Kaposi's sarcoma in mice by overexpressing a single protein. The researchers found that as mice age, overexpression of Rac1, in a form that is constitutively activated, triggers the development of a tumor that has all the scientific characteristics of human Kaposi's sarcoma.

"The protein Rac1 triggers the activation of an enzyme that produces superoxide, a strong oxidant which leads to molecular reactions that promote the proliferation of tumor cells that exactly resemble human Kaposi's sarcoma," explains Enrique Mesri, Ph.D., associate professor of microbiology and immunology at the Miller School and Sylvester and corresponding author of the study. "Superoxide and derived reactive oxygen species (ROS), which are strong oxidants that cause damage at the molecular level, can also damage the DNA and prevent the expression of tumor suppressor genes such as p53."

The production of these strong oxidants also triggers the overexpression of hypoxia-inducible factor-1 alpha (HIF1-a which regulates the expression of molecules that enhance angiogenesis, the process by which new blood vessels feed a tumor leading to its malignancy. After understanding the molecular pathways of Kaposi's sarcoma, the scientists set out to determine if the oxidant ROS were directly related to the development of the cancer.

"We gave half the mice regular water, while the other half received water supplemented with the antioxidant N-acetyl cysteine (NAC)," explains Qi Ma, Ph.D., postdoctoral associate at the Miller School and lead author of the study. "The mice given the antioxidant never grew tumors, and in the ones that had tumors the NAC prevented them from growing."

NAC is known to promote the reduction of glutathione, which is an important cellular re-agent that buffers the oxidation of protein in cells. Reduced glutathione can prevent the oxidation of proteins, allowing NAC to suppress tumor development and growth.

"Our study provides not only a new understanding of the molecular pathways that are contributing to the formation of Kaposi's sarcoma lesions, but it also suggests mechanisms by which Kaposi's sarcoma lesions could be prevented in patients with HIV or other susceptibilities," said Miller School Dean Pascal J. Goldschmidt, M.D., who is also a corresponding author of the study. "The scientific team will continue to investigate the possibility that NAC and other antioxidants could help prevent and suppress the growth of Kaposi's sarcoma lesions. We are also looking at additional molecular mechanisms that contribute to Kaposi's sarcoma to more effectively intervene in the development of this dreadful cancer."

Source
University of Miami Miller School of Medicine

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