Lani
05-04-2007, 09:00 AM
antifungal pill works vs. cholesterol formation (article unsure of e
xact mechanism of action, but implies it may be like statins, which are also angiogenesis inhibitors)--translation: they inhibit the formation of new blood vessels that cancers need to recruit in order for the cancer to grow beyond a certain size and then metastasize
Antifungal Drug Stops Blood Vessel Growth [Johns Hopkins Medical Institutions]
Researchers at Johns Hopkins have discovered to their surprise that a drug commonly used to treat toenail fungus can also block angiogenesis, the growth of new blood vessels commonly seen in cancers. The drug, itraconazole, already is FDA approved for human use, which may fast-track its availability as an antiangiogenesis drug.
In mice induced to have excess blood vessel growth, treatment with itraconazole reduced blood vessel growth by 67 percent compared to placebo. "We were surprised, to say the least, that itraconazole popped up as a potential blocker of angiogenesis," says Jun O. Liu, Ph.D., professor of pharmacology. "We couldn't have predicted that an antifungal drug would have such a role."
In their search for antiangiogenesis drugs, the researchers worked with cells from human umbilical cords, a rich source of blood vessels, and exposed them to 2,400 existing drugs - including FDA- and foreign-approved drugs, as well as nonapproved drugs that had passed safety trials - to see which ones could stop the cells from dividing.
"The best outcome was to find an already approved drug that worked, and the fact that we did was very satisfying," says Liu, whose study appears online in ACS Chemical Biology. As an antifungal drug, itraconazole blocks a key enzyme for making fungal cholesterol, causing these primitive life forms to become fragile and break apart. It turns out that itraconazole can block the same enzyme in blood vessels, but the researchers aren't positive if that's the reason blood vessels stop growing, because related antifungal drugs had much lower inhibitory effect.
"Our screening test did show that cholesterol-lowering statins also appear to stop blood vessel growth," Liu says, "so there is likely some important connection between cholesterol and angiogenesis." While the researchers still must tease out exactly how itraconazole works to stop vessel growth, and test it in animals with cancer, they have high hopes for its use. "Itraconazole can be taken orally for fungal infection, and therefore oral delivery may work for angiogenesis as well," Liu notes.
The research was funded by the Johns Hopkins School of Medicine, the Johns Hopkins Fund for Medical Discovery, the Johns Hopkins Malaria Research Institute, the Keck Foundation, and the Flight Attendant Medical Research Institute Fund.
Authors on the paper are Curtis Chong, Jing Xu, Jun Lu, Shridhar Bhat, David Sullivan Jr. and Jun O. Liu, all of Johns Hopkins.
ABSTRACT: Inhibition of Angiogenesis by the Antifungal Drug Itraconazole [ACS Chemical Biology]
Angiogenesis, the formation of new blood vessels, is implicated in a number of important human diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis. To identify clinically useful angiogenesis inhibitors, we assembled and screened a library of mostly Food and Drug Administration-approved drugs for inhibitors of human endothelial cell proliferation. One of the most promising and unexpected hits was itraconazole, a known antifungal drug. Itraconazole inhibits endothelial cell cycle progression at the G1 phase in vitro and blocks vascular endothelial growth factor/basic fibroblast growth factor-dependent angiogenesis in vivo. In attempts to delineate the mechanism of action of itraconazole, we found that human lanosterol 14?-demethylase (14DM) is essential for endothelial cell proliferation and may partially mediate the inhibition of endothelial cells by itraconazole. Together, these findings suggest that itraconazole has the potential to serve as an antiangiogenic drug and that lanosterol 14DM is a promising new target for discovering new angiogenesis inhibitors.
xact mechanism of action, but implies it may be like statins, which are also angiogenesis inhibitors)--translation: they inhibit the formation of new blood vessels that cancers need to recruit in order for the cancer to grow beyond a certain size and then metastasize
Antifungal Drug Stops Blood Vessel Growth [Johns Hopkins Medical Institutions]
Researchers at Johns Hopkins have discovered to their surprise that a drug commonly used to treat toenail fungus can also block angiogenesis, the growth of new blood vessels commonly seen in cancers. The drug, itraconazole, already is FDA approved for human use, which may fast-track its availability as an antiangiogenesis drug.
In mice induced to have excess blood vessel growth, treatment with itraconazole reduced blood vessel growth by 67 percent compared to placebo. "We were surprised, to say the least, that itraconazole popped up as a potential blocker of angiogenesis," says Jun O. Liu, Ph.D., professor of pharmacology. "We couldn't have predicted that an antifungal drug would have such a role."
In their search for antiangiogenesis drugs, the researchers worked with cells from human umbilical cords, a rich source of blood vessels, and exposed them to 2,400 existing drugs - including FDA- and foreign-approved drugs, as well as nonapproved drugs that had passed safety trials - to see which ones could stop the cells from dividing.
"The best outcome was to find an already approved drug that worked, and the fact that we did was very satisfying," says Liu, whose study appears online in ACS Chemical Biology. As an antifungal drug, itraconazole blocks a key enzyme for making fungal cholesterol, causing these primitive life forms to become fragile and break apart. It turns out that itraconazole can block the same enzyme in blood vessels, but the researchers aren't positive if that's the reason blood vessels stop growing, because related antifungal drugs had much lower inhibitory effect.
"Our screening test did show that cholesterol-lowering statins also appear to stop blood vessel growth," Liu says, "so there is likely some important connection between cholesterol and angiogenesis." While the researchers still must tease out exactly how itraconazole works to stop vessel growth, and test it in animals with cancer, they have high hopes for its use. "Itraconazole can be taken orally for fungal infection, and therefore oral delivery may work for angiogenesis as well," Liu notes.
The research was funded by the Johns Hopkins School of Medicine, the Johns Hopkins Fund for Medical Discovery, the Johns Hopkins Malaria Research Institute, the Keck Foundation, and the Flight Attendant Medical Research Institute Fund.
Authors on the paper are Curtis Chong, Jing Xu, Jun Lu, Shridhar Bhat, David Sullivan Jr. and Jun O. Liu, all of Johns Hopkins.
ABSTRACT: Inhibition of Angiogenesis by the Antifungal Drug Itraconazole [ACS Chemical Biology]
Angiogenesis, the formation of new blood vessels, is implicated in a number of important human diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis. To identify clinically useful angiogenesis inhibitors, we assembled and screened a library of mostly Food and Drug Administration-approved drugs for inhibitors of human endothelial cell proliferation. One of the most promising and unexpected hits was itraconazole, a known antifungal drug. Itraconazole inhibits endothelial cell cycle progression at the G1 phase in vitro and blocks vascular endothelial growth factor/basic fibroblast growth factor-dependent angiogenesis in vivo. In attempts to delineate the mechanism of action of itraconazole, we found that human lanosterol 14?-demethylase (14DM) is essential for endothelial cell proliferation and may partially mediate the inhibition of endothelial cells by itraconazole. Together, these findings suggest that itraconazole has the potential to serve as an antiangiogenic drug and that lanosterol 14DM is a promising new target for discovering new angiogenesis inhibitors.