Abstract
The antihelmintic drug ABZ and its metabolites belong to the chemical family of benzimidazoles (BZM) that act as potent tubulin polymerization inhibitors, suggesting a potential re-direction of BZMs for cancer therapy. Applying UV-Vis spectrometry we here demonstrate ABZ as a DNA intercalator. This insight led us to determine the primary mode of ABZ action in mammalian cells. As revealed by RNA sequencing, ABZ did neither grossly affect replication as analyzed by survival and replication stress signaling, nor the transcriptome. Actually, unbiased transcriptome analysis revealed a marked cell cycle signature in ABZ exposed cells. Indeed, short-term exposure to ABZ arrested mammalian cells in G2/M cell cycle stages associated with frequent gains and losses of chromatin. Cellular analyses revealed ABZ as a potent mammalian spindle poison for normal and malignant cells, explaining the serious chromosome segregation defects. Since chromosomal aberrations promote both cancer development and cell death, we determined if besides its general cytotoxicity, ABZ could predispose to tumor development. As measured by loss of heterozygosity (LOH) in vitro and in vivo ABZ was found as a potent inducer of LOH and accelerator of chromosomal missegregation.
Highlights
While ABZ acts as a tubulin polymerization inhibitor in helminth, its effect in mammalian cells is poorly understood
If ABZ is a DNA intercalator, one predicts that ABZ competes with the DNA intercalator ethidium bromide (EtBr), a widely applied fluorescent dye to visualize and measure DNA
Since the FDA approval of ABZ in 1982 for the treatment of helminthiasis in humans, ABZ developed as an affordable drug that is currently manufactured and distributed by 385 companies, reflecting the necessity of affordable drugs in treating STH as well as lymphatic filariasis infections (Dayan, 2003)
Summary
ABZ developed as an affordable drug that is currently manufactured by 385 companies and distributed under at least 626 brand names listed in the Medindia’s database (Medindia, 2017) These large numbers reflect the necessity of affordable drugs in treating soil transmitted helminth (STH) as well as lymphatic filariasis infections. Other WHO data report preventive chemotherapy of (pre)school-aged children with ABZ as a ABZ: A Potent LOH Inducer monotherapy or in combination with another drug, in many areas of the world These data highlight the global challenge of STH to mankind, the current importance of ABZ chemotherapy in fighting STH infections in humans, and its extensive global use (Supplementary Figure S1) (for more information we like to refer readers of this study to the WHO website (World Health Organization, 2020c)
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