Repositioning of chlorambucil as a potential anti-schistosomal agent

Abstract

As parasites and cancer cells share many lifestyle and behavioral resemblances, repositioning of anti-cancerous agents as anti-parasitic is quite trendy, especially those sharing the same therapeutic targets. Therefore, the current study investigated the in vitro efficacy of ascending concentrations of chlorambucil (0.5–20μg/ml) against adult Schistosoma mansoni worms, over 72h. Additionally, its in vivo effects against the different developmental stages of the worm were assessed, after an oral dose of 2.5mg/kg/day for five successive days, through evaluating the worm load reduction and worms' morphological alterations and oogram changes. In addition to tissue egg count, a histopathological study of the liver was conducted. In vitro, chlorambucil demonstrated noticeable anti-schistosomal effects in the form of progressive reductions of the worms' viability in a dose dependent manner. Complete worm death was achieved at 72h incubation with 5μg/ml drug concentration. In vivo, chlorambucil induced a significant reduction in the total worm load against all developmental stages. Its highest impact was evident against the juvenile stage, where it induced 75.8% total worm load reduction, and 89.2% and 86.7% intestinal and hepatic egg counts reduction, respectively, along with ogram alterations. Besides, it induced significant shortening of both male and female worms and promoted an amelioration of hepatic histopathology. Results show that chlorambucil possesses favorable in vitro and in vivo anti-schistosomal activity. The highest in vivo efficacy was against the juvenile stage of S. mansoni, significantly superior to praziquantel, with extended potency to the adult stage. Further studies are recommended for chlorambucil target verification and to enhance its therapeutic efficacy.