A quickly growing tumor eventually outgrows its blood supply and encounters a lack of oxygen. However, these conditions actually help a tumor survive, because radiation and chemotherapy are less effective under low oxygen conditions. Also, low oxygen drives cancer cells to send out signals that attract new blood vessels.
Researchers at Emory Winship Cancer Institute have identified a chemical that stops cells from making HIF1α (hypoxia-inducible factor 1-alpha), a key part of cells' machinery for responding to hypoxia, or conditions of low oxygen.
The results are online and scheduled for publication in the Oct. 1, 2009 issue of Clinical Cancer Research. Under the influence of the compound KC7F2, which is toxic to several types of cancer cells, tumors essentially don't know that they're suffocating because they can't make HIF1α. The structure of KC7F2 is related to that of psammaplin A, a compound isolated from marine sponges that also has antitumor properties.
HIF1α is part of a transcription factor that turns on other genes and is normally unstable and scarce, but low oxygen conditions make it more stable. In low oxygen, HIF1α joins with a partner (HIF1α) to encourage new blood vessel growth and reshape cells' metabolism.
"The scientific community has been searching for small molecules that can specifically inhibit the function of HIF because it is essential for tumor growth under hypoxia," says Erwin Van Meir, PhD, professor of neurosurgery and hematology and medical oncology at Emory Winship Cancer Institute. "This is quite challenging as transcription factors are hard to target directly. A different approach is to prevent HIF synthesis, and KC7F2 acts in this fashion." Working with Van Meir, postdoctoral researchers Takuhito Narita and Shaoman Yin, in collaboration with Dr. K.C. Nicolaou's group at the Scripps Research Institute in San Diego, sifted through thousands of chemicals to find one that counteracts HIF1α. More studies to determine exactly how KC7F2 prevents HIF1α synthesis and whether it will be effective in vivo are planned.
The authors write: "The identification and development of novel HIF-1 pathway inhibitors may lead to the development of a new type of treatment for cancer, potentially applicable to many solid malignancies." The research was supported by the National Institutes of Health, the American Brain Tumor Association, the Brain Tumor Foundation for Children, the Charlotte Geyer Foundation and the Southeastern Brain Tumor Foundation. Reference: T. Narita et al. Identification of a Novel Small Molecule HIF-1α Translation Inhibitor Clin. Canc. Res. 15 :6128-36 (2009).