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Inhibition Of Iron-metabolizing Enzyme Reduces Tumor Growth

A report in the Journal of Biological Chemistry shows that inhibition of heme oxygenase-1, an enzyme involved in iron metabolism, reduces Kaposi sarcoma tumor growth. This discovery could result in the production of new drugs to treat this and other viral cancers.

This research appears as the "Paper of the Week" in the April issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

Kaposi sarcoma is the most frequent tumor in AIDS patients and is caused by infection of the patients with the Kaposi sarcoma-associated herpes virus. The Kaposi sarcoma virus genome contains sequence that encodes for a protein called viral G protein-coupled receptor (vGPCR) that plays a key role in the development of tumoral lesions.

Interestingly, a study done in early 2004 showed that the cellular production of a protein called heme oxygenase-1 could be turned on by the Kaposi's sarcoma-associated herpesvirus. Heme oxygenase-1 is an enzyme that is expressed in spleen and liver and is responsible for breaking down heme, a molecule that consists of an iron atom surrounded by a large ring of other atoms. Further evidence of the connection between heme oxygenase-1 and the Kaposi's sarcoma virus came when elevated levels of the protein were detected in biopsy tissue from oral AIDS-Kaposi's sarcoma lesions.

"Taking into account the predominant function of vGPCR in Kaposi's sarcoma and the elevated expression of heme oxygenase-1 observed in Kaposi's sarcoma lesions, we decided to study whether vGPCR could increase heme oxygenase-1 expression and if so, to explore the putative role of the enzyme in vGPCR-dependent transformation," explains study author Maria Julia Marinissen of the Universidad Autonoma de Madrid.

Marinissen and her colleagues found that vGPCR does indeed increase production of the heme oxygenase-1 protein and the RNA that codes for it. They also discovered that mice with tumors that were given specific pharmacological inhibitors that blocked heme oxygenase-1 activity showed a significant reduction in tumor growth without apparent side effects.

"Considering that heme oxygenase-1 is overexpressed in human Kaposi's sarcoma lesions, the inhibition of intratumoral heme oxygenase-1 activity by currently available drugs can represent a new anticancer tactic in the treatment of Kaposi's sarcoma and may be of potential clinical interest after more extensive investigation," says Marinissen. "The inhibitor that we used in this study is a tin-protoporphyrin. A recent clinical trial showed that the inhibitor can be administered to newborns at any time point in the progression of postnatal hyperbilirubinemia to rapidly and predictably block heme degradation and prevent severe jaundice without significant short- or long-term side effects. This is very important because it shows that the inhibitor has been successfully used in human clinical trials to treat diseases in which heme oxygenase-1 is involved."


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