Researchers at Massachusetts General Hospital (MGH) have discovered an entirely new class of antiangiogenesis drugs – agents that interfere with the development of blood vessels- in a compound found in a South American tree.
They described how this compound called dehydro-alpha-lapachone (DAL), derived from Tabebuia avellanedae, a tree native to Argentina and Brazil, was able to help wound healing and inhibit tumor growth in animal models.
“Most of the FDA-approved antiangiogenesis drugs inhibit the pathway controlled by vascular endothelial growth factor or VEGF, which directly stimulates blood vessel development,” said Igor Garkavtsev, MD, PhD, of the Steele Laboratory for Tumor Biology at MGH and lead author of the study.
Garkavtsev and his colleagues first showed that DAL administration interfered with blood vessel formation in zebrafish, both during embryonic development and wound healing.
Tabebuia avellanedae
They then found that it reduced the vascular density of tumors implanted in mice and, with daily treatment, significantly reduced tumor growth with no signs of toxicity.
Experiments with endothelial cells from human umbilical veins revealed that DAL administration altered the size and shape of the cells by changing the organization of the actin cytoskeleton; blocked formation of new vascular networks and reorganized existing networks; and interfered with the movement of cells required for wound healing.
Further investigation found that DAL produces these effects by decreasing the activity of Rac1, a protein known to be important to cellular adhesion and cytoskeletal organization.
“DAL has the potential to improve treatment of many types of cancer and of other diseases characterized by abnormal blood vessels,” concluded Rakesh Jain, PhD, director of the Steele Lab and senior author of the study.
The finding was reported in Proceedings of the National Academy of Sciences/Early Edition.
