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

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.

Inhibitors of Tyrosine Kinases (TKI) and Small Interfering RNAs (siRNA) are Promising Targeted Cancer Treatments

“…Because of its relative short history, it is too early to predict the therapeutic usefulness of RNA interference, although there is evidence that it may produce selective post-transcriptional inhibition in vivo. Thus, down-regulation of different proteins has been shown to reduce the tumor growth rate, and has in some cases also led to a reduced tumor size [1,2]. In any event, the efficient delivery of such drugs to the target cells will constitute a challenge of vast proportions.…”

“…A few years ago almost all cancer drugs were directed against metabolic enzymes or the stability of the DNA strand. Late in the 1990s therapy targeting DNA topoisomerases had some success [1]. In addition to such therapy, the very common cancers of the breast and prostate, have been treated by interfering with hormonal signaling pathways via nuclear hormone receptors.…”

A “Double-Edged” Scaffold: Antitumor Power within the Antibacterial Quinolone

“…Therefore, it may not be entirely surprising that there exist “dual” agents which interact with both topo I and topo II. Experimental dual-acting agents have been described in the literature, although none have yet been commercialized [158, 159]. In 1990, during the early profiling of clinical antibacterial quinolones against human topoisomerases, topo I inhibition by these drugs was measured but was found to be weak [117, 160, 161].…”

Antiproliferative and apoptosis-inducing activities of novel naphthalimide–cyclam conjugates through dual topoisomerase (topo) I/II inhibition

“…In this regard, compounds which have the potential to simultaneously inhibit topoisomerase I and II attracted great attention to improve antitumor activities and to overcome drug resistance problem. 8,[14][15][16][17] Macrocyclic derivatives, especially tetraazamacrocycles are applied in medical use. Cyclam (1,4,8,11- …”