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Caption: Chemotherapeutic drugs/ionizing radiation and curaxins interact with cellular DNA. However the former cause DNA breaks and the latter change architecture of DNA and chromatin without actual breaks. DNA breaks interfere with proliferation of tumor cells (DNA cannot be packed and appropriately and divided between two daughter cells). In addition DNA breaks are sensed by DNA-damaging sensitive kineses as major stress. Activated kinases may induce tumor cell death (through activation of cell death pathways, such as p53) but also may activate adaptive pro-survival response pathways (such as NF-kB). Unfortunately in tumor cells p53 is frequently inactivated through mutations or due to high activity of NF-kB, which suppress p53 function. Therefore DNA breaks in tumor cells results in activation of NF-kB, additional suppression of p53 and mutations. Mutations in survived tumor cells lead to the emergence of resistance to the therapy and in normal cells to side effects and secondary cancers. Change in chromatin structure in curaxin treated cells is sensed by DNA structure sensitive FACT complex. FACT binds strongly to distorted chromatin in curaxin treated tumor cells, what leads to activation of p53 and death pathways, inhibition of NF-kB and suppression of pro-survival adaptive response. At the same time there is no induction of mutations and promoting of therapy resistance. Therefore we believe that use of curaxins may make anticancer therapy more efficacious and safe comparing with current chemotherapy. This image relates to a paper that appeared in the Aug. 10, 2011, issue of Science Translational Medicine, published by AAAS. The paper, by Dr. A.V. Gasparian of Cleveland BioLabs Inc. in Buffalo, N.Y., and colleagues, was titled, "Curaxins: Anticancer Compounds that Simultaneously Suppress NF-kB and Activate p53 by Targeting FACT."
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