Curaxins Study Points to FACT as Promising Target for Anticancer Drugs

Cancer researchers have discovered how curaxins, a promising new category of anticancer drugs, act at the molecular level to prevent cells from becoming cancerous.

Previous studies had shown that the curaxins inhibit tumor growth and division by both activating the tumor suppressing p53 pathway and by blocking the tumor generating nuclear factor kappaB (NF-kappaB) pathway. These two pathways have been found to malfunction in many types of cancer.

Curaxins tested in animal models were so potent that they were effective against all tested human tumor xenografts grown in mice while not causing damage to DNA of normal cells. In the current study, investigators at Roswell Park Cancer Institute (Buffalo, NY, USA) and at Cleveland BioLabs, Inc. (Buffalo, NY, USA) focused on how the curaxins function so successfully at the molecular level to activate p53 while inhibiting NF-kappaB.

They reported in the August 10, 2011, online edition of the journal Science Translational Medicine that the effects of curaxins on p53 and NF-kappaB, as well as their toxicity to cancer cells, resulted from “chromatin trapping” of the FACT (facilitates chromatin transcription) protein complex. This FACT inaccessibility leads to activation of p53 through phosphorylation of p53 at the Ser392 amino acid residue by casein kinase-2 and inhibition of NF-kappaB–dependent transcription, which requires FACT activity at the elongation stage. FACT thus emerges as a prospective anticancer target enabling simultaneous modulation of several pathways frequently dysregulated in cancer without induction of DNA damage.

“By hitting multiple cancer treatment targets, curaxins resemble long-known and very efficacious anticancer drugs such as doxorubicin or cisplatin, but without their genotoxicity, which is the main challenge of historical chemotherapies,” said contributing author Dr. Andrei V. Gudkov, chief scientific officer of Cleveland BioLabs, Inc. “Our studies continue to reinforce our belief that curaxins are promising drug candidates that may be effective against a wide range of cancer types.”

Related Links:
Roswell Park Cancer Institute
Cleveland BioLabs, Inc.