New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents

Abstract

Most of the anticancer chemotherapeutic drugs that are broadly and successfully used today are DNA-damaging agents. Targeting of DNA has been proven to cause relatively potent and selective destruction of tumor cells. However, the clinical potential of DNA-damaging agents is limited by the adverse side effects and increased risk of secondary cancers that are consequences of the agents' genotoxicity. In this review, we present evidence that those agents capable of targeting DNA without inducing DNA damage would not be limited in these ways, and may be as potent as DNA-damaging agents in the killing of tumor cells. We use as an example literature data and our own research of the well-known antimalarial drug quinacrine, which binds to DNA without inducing DNA damage, yet modulates a number of cellular pathways that impact tumor cell survival.

Figure 1. Compounds discussed in the text

(A) Structure of the compound identified in the screening of p53 activators. This compound was in Diversity Set Small Molecule Library (Chembridge, San Diego, CA, USA) ID# 561611. Treatment of renal cell carcinoma cells with this compound induced p53-dependent reporter activity. (B) Known compounds with 9-aminoacridine scaffold used in medicine for different purposes. 9-aminoacridine – antiseptic, acriflavin – experimental anticancer compound, amsacrine – anticancer drug, inhibitor of topoisomerase II and quinacrine – antimalarial and anti-inflammatory agent.

Figure 2. DNA-binding capacity of quinacrine enantiomers correlates with p53 activation and NF-κB inhibition

(A) Computer modeling of the fitness for R- and S-isomer binding to double-stranded DNA. The average fitness of R conformers is 7% better than that of S conformers, (p < 0.00001). The better fitness of R conformers is primarily due to one of the fitness score components; van der Waals potential energy between ligand and DNA atoms. It is also likely that the S isomer disrupts DNA Watson–Crick pairing through hydrogen bonding by the nitrogen in quinacrine (QC)'s tail. Modeling was carried out by L Brodsky (Cleveland BioLabs, NY, USA). (B) Binding of QC isomers and racemic mixture to plasmid DNA in a competitive dialysis experiment. 30 μM double stranded plasmid DNA were placed in a mini-dialysis unit (Pierce, #69560) and dialyzed for 24 h against 200 ml of 1 mM QC solution. DNA-bound QC was measured by fluorimetry. The multiple curves represent replicates of the experiment. The fluorescence on Y-axis reflects the amount of QC bound by DNA. Experiment was carried out by A Gasparian (Cleveland BioLabs, NY, USA). (C) Activation of p53-dependent luciferase reporter in RCC45 cells by QC isomers. (D) Inhibition of NF-κB reporter in H1299 cells by QC isomers. Error bars in (C) and (D) show the standard error between eight replicates of experiment. Reporter activity was measured 24 h after chemicals were added by Promega (WI, USA) Bright-Glo™ assay. Experiments (C) and (D) were performed by D Bosykh (Cleveland BioLabs, NY, USA).