Structural determinants of the catalytic inhibition of human topoisomerase IIα by salicylate analogs and salicylate-based drugs.
We previously identified salicylate as a novel catalytic inhibitor of human DNA topoisomerase II (topo II; EC 5.99.1.3) that preferentially targets the alpha isoform by interfering with topo II-mediated DNA cleavage. Many pharmaceuticals and compounds found in foods are salicylate-based. We have now investigated whether these are also catalytic inhibitors of topo II and the structural determinants modulating these effects. We have determined that a number of hydroxylated benzoic acids attenuate doxorubicin-induced DNA damage signaling mediated by the ATM protein kinase and inhibit topo II decatenation activity in vitro with varying potencies. Based on the chemical structures of these and other derivatives, we identified unique properties influencing topo II inhibition, including the importance of substitutions at the 2'- and 5'-positions. We extended our findings to a number of salicylate-based pharmaceuticals including sulfasalazine and diflunisal and found that both were effective at attenuating doxorubicin-induced DNA damage signaling, topo II DNA decatenation and they blocked stabilization of doxorubicin-induced topo II cleavable complexes in cells. In a manner similar to salicylate, we determined that these agents inhibit topo II-mediated DNA cleavage. This was accompanied by a concomitant decrease in topo II-mediated ATP-hydrolysis. Taken together, these findings reveal a novel function for the broader class of salicylate-related compounds and highlight the need for additional studies into whether they may impact the efficacy of chemotherapy regimens that include topo II poisons.
Southern Alberta Cancer Research Institute and Department of Physiology & Pharmacology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
Jason T
JT
Bau
Southern Alberta Cancer Research Institute and Department of Physiology & Pharmacology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. Electronic address: kurz@ucalgary.ca.
Ebba U
EU
Kurz
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D043864:DNA, Catenated / Q000737:chemistry / Q000378:metabolism; D018105:DNA, Kinetoplast / Q000737:chemistry / Q000378:metabolism; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004061:Diflunisal / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D012459:Salicylates / Q000737:chemistry* / Q000494:pharmacology; D012980:Sodium Salicylate / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D012460:Sulfasalazine / Q000737:chemistry / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D043864:DNA, Catenated; D018105:DNA, Kinetoplast; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D012459:Salicylates; D012460:Sulfasalazine; D004061:Diflunisal; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D004250:DNA Topoisomerases, Type II; D012980:Sodium Salicylate
Catalytic inhibitor; Diflunisal; Salicylate; Sulfasalazine; Topoisomerase II