Acriflavine Blocks Tumor Growth by Preventing Blood Vessel Formation

As a result of a program to revisit and reevaluate old drugs, acriflavine, a topical antiseptic once used to treat gonorrhea, was found to slow tumor growth by blocking the formation of new blood vessels.

Investigators at the Johns Hopkins University School of Medicine (Baltimore, MD, USA) used a cell-based screening assay to test compounds in the Johns Hopkins Drug Library, a collection of FDA- and internationally approved compounds, for their ability to inhibit tumor growth. A positive result was obtained for acriflavine, a topical antiseptic developed in 1912 by Paul Ehrlich.

Results published in the October 1, 2009, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) revealed that pretreatment of mice bearing prostate cancer xenografts with acriflavine prevented tumor growth, and treatment of mice bearing established tumors resulted in growth arrest. Acriflavine acted directly on the protein hypoxia-inducible factor (HIF)-1, which in cells under oxygen stress activates genes that generate new blood vessels. Many types of cancer cells express HIF-1, as rapidly growing tumors require a constant supply of oxygen and nutrients.

Acriflavine was found to bind directly to HIF-1-alpha and HIF-2-alpha and inhibited HIF-1 dimerization and transcriptional activity. In the mouse xenograft model acriflavine treatment inhibited intratumoral expression of angiogenic cytokines, mobilization of angiogenic cells into peripheral blood, and tumor vascularization.

"Often times we are surprised that a drug known to do something else has another hidden property,” said contributing author Dr. Jun Liu, professor of pharmacology and molecular sciences at Johns Hopkins University. "Mechanistically, this is the first drug of its kind. It is acting in a way that is never seen for this family of proteins.”

"In the public domain, Hopkins has the largest drug library," said Dr. Liu. "The more drugs you have, the more possibilities, the higher the chance you rediscover something that will help.”

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