Role of c-trapping in anti-cancer activity of DNA-targeting drugs: Correlative study
Aljahdali, Ieman A.
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C-trapping is a phenomenon of chromatin trapping or tight binding of histone chaperone FACT to chromatin in cells treated with anti-cancer small molecule curaxins. Curaxin binds DNA, and while it does not cause DNA damage, it does alter the helical structure of DNA resulting in nucleosome and chromatin disassembly. C-trapping and the associated loss of chromatin organization in tumor cells is responsible for the anti-cancer activity of curaxins and presents a novel mechanism of anti-cancer agent. Potentially the binding of other molecules to DNA may also cause c-trapping since at least some of them also alter helical structure of DNA. This study aims to examine the role of c-trapping in the anti-cancer activity of DNA-targeting drugs by answering the following three questions: (1) which DNA-targeting agents cause c-trapping? (2) Is there a difference between the toxic range of these agents and those that cause c-trapping? (3) Are the kinetics of c-trapping caused by these agents comparable? This study hypothesizes that C-trapping may be caused by changes in DNA structure induced by other DNA binding with small molecules and may play a role in the anti-cancer activity of these agents. Prior studies have shown that cisplatin causes different types of changes in the DNA’s helical structure, also leading to c-trapping. This study advances our understanding of how commonly used anticancer agents that target DNA kill or inhibit cancer growth. To test our hypothesis, we conducted cytotoxicity assays using the following agents: aclacinomycin A, bleomycin, doxorubicin, etoposide, gemcitabine, Hoechst 333342, ICRF-139, merbarone, mitoxantrone, and SN38. These represent different classes of DNA-targeting agents in order to identify the toxic range for each drug. To test whether these drugs cause c-trapping or not, we developed a western blot based c-trapping assay. We showed that c-trapping is caused by some of the tested drugs only if they directly bind DNA. Our findings support the model of c-trapping as a phenomenon that dependents on a change in the 3D helical structure of DNA caused by small molecule binding. It also suggests that c-trapping may be involved in the mechanism of anti-cancer activity of these agents and prompt a re-thinking of these agents’ mechanisms of action.