Recent Advances in the Development of Dual Topoisomerase I and II Inhibitors as Anticancer Drugs

S.      Salerno; F.      Da Settimo; S.      Taliani; F.      Simorini; C.      La Motta; G.      Fornaciari; A.      M. Marini

Abstract

DNA topoisomerases (topos) are essential enzymes that regulate the topological state of DNA during cellular processes such as replication, transcription, recombination, and chromatin remodeling. Topoisomerase I (Topo I) is a ubiquitous nuclear enzyme which catalyzes the relaxation of superhelical DNA generating a transient single strand nick in the duplex, through cycles of cleavage and religation. Topoisomerase II (Topo II) mediates the ATP-dependent induction of coordinated nicks in both strands of the DNA duplex, followed by crossing of another double strand DNA through the transiently broken duplex. Although the biological functions of Topoisomerases are important for ensuing genomic integrity, the ability to interfere with enzymes or generate enzyme-mediated damage is an effective strategy for cancer therapy and, in this connection, DNA topos (I and II) proved to be the excellent targets of clinically significant classes of anticancer drugs. Actually, specific Topo I and Topo II inhibitors reversibly trap the enzyme-DNA complexes, thus converting topos into physiological poisons, able to produce permanent DNA damage, which triggers cell death. Given that both enzymes are good targets, it would be desirable to jointly inhibit them, but use-limiting toxicity of sequential or simultaneous combinations of Topo I and II poisons include severe to life-threatening neutropenia and anemia. Furthermore, the emergence of resistance phenomena to Topo I inhibitors is often accompanied by a concomitant rise in the level of Topo II expression and viceversa, leading to the failure of clinical therapies. In this regard, a single compound able to inhibit both Topo I and II may present the advantage of improving antitopoisomerase activity, with reduced toxic side effects, with respect to the combination of two inhibitors. Due to the high interest in such compounds, this review represents an update of previous works dealing with the development of dual Topo I and II inhibitors as novel anti-cancer agents. The newly collected derivatives have been described focusing attention on their chemical structures and their biological profiles.

Keywords: Anticancer drugs, Antiproliferative activity, Dual inhibitor, Topoisomerase II, Topoisomerase I, replication, transcription, recombination, chromatin remodeling, neutropenia, anemia, apoptosis, DNA, Topisomerase IV, Etoposide, Ellipticine 5, chromophore, Amsacrine, Quinolones, Diflomotecan, Gimatecan, leukaemia, Irinotecan, Tafluposide, xenografts, solid tumours, cisplatin, HL-60 human promyelocytic leukaemic cells, Batracylin, adenocarcinomas, MDR phenomena, Phenazine Derivatives, MTDs, pharmacokinetics, Doxorubicin, Camptothecin, Topotecan, Paclitaxel, Carboplatin, Prodigiosin, S. marcescens, Curcumin, malignant, enzymes, cytotoxic, Tilia amurensis, Topopyrones, pluramycins, human leukaemia cells (CEM), G2/M phases, Mitoxanthrone, Apigenin, Fisetin, Myricetin, Daunorubicin (DAU), cardiotoxicity, Camptothecins