Protein Kinases as Potential Targets for Novel Anti-Schistosomal Strategies

Abstract

Schistosome parasites are the causative pathogens of schistosomiasis (bilharzia), a disease of worldwide significance. In terms of patient numbers, schistosomiasis ranks second to malaria as a parasitosis affecting more than 200 million people of the tropics and subtropics. Since the 1970s Praziquantel (PZQ) is the drug of choice and nearly exclusively used for treatment. However, drug resistance is an increasing threat, particularly with respect to large-scale PZQ administration programs. Last decade´s research indicated that resistance against PZQ can be induced under laboratory conditions, and field studies provided first indications for the possibility of reduced PZQ efficacy. Furthermore, clear evidence for the molecular armamentarium of schistosomes with multidrug transporters was found, one of which was responding to PZQ challenge. Also the development of a vaccine still represents an elusive goal, although effort and time have been invested in this subject. In light of these facts it is commonly accepted that new drugs are urgently needed. Research on signal transduction processes in Schistosoma mansoni has provided an unexpected and novel perspective towards this end. Molecular, biochemical, and physiological studies elucidating principles of schistosome development have demonstrated the essential role of protein kinases (PKs). In humans, PKs are known to be involved in cancer development. Since a variety of approved anticancer drugs targeting PKs exist, first studies have been performed to investigate whether these drugs are able to also inhibit schistosome PKs. Indeed, promising results have been obtained indicating the potential of PKs as privileged targets for new concepts in fighting schistosomes.

Imatinib Treatment Causes Substantial Transcriptional Changes in Adult Schistosoma mansoni In Vitro Exhibiting Pleiotropic Effects

“…This was confirmed by an independent approach recently, which reproduced similar phenotypes in vitro , although a first in vivo experiment failed [106]. Nonetheless, the data obtained in this study support the conclusion that Imatinib exerts broad negative effects on worm physiology substantiating the hypothesized role of PKs as potential targets [25], [28], [36], [42], [43]. In this respect it was encouraging to note that according to our microarray analysis also multidrug resistance (MDR) genes (Smp_089200, Smp_151290) were among the significantly down-regulated genes following Imatinib treatment.…”

Compound library screening identified Akt/PKB kinase pathway inhibitors as potential key molecules for the development of new chemotherapeutics against schistosomiasis

“…They are involved in many biological processes such as cell growth, proliferation and differentiation. In schistosomes, PKs have been shown to play major roles in development and reproduction processes ( Beckmann et al, 2012; Dissous et al, 2014a ). Targeting of diverse PKs was shown to affect reproductive biology of parasites, as well as survival of adult worm and/or schistosomula in vitro , supporting the hypothesis that PK inhibitors are potential chemotherapeutics against schistosomiasis ( Dissous and Grevelding, 2011 ).…”

“…Their biochemical characteristics are well studied due to their importance in cancer, and a large variety of small molecules targeting selectively kinase activities is now commercially available and already used for human cancer therapy ( Johnson, 2009 ). In schistosomes, many studies have shown that PKs are implicated in essential functions at every stage of the parasite life cycle, and that these enzymes represent suitable anti-parasite drug targets ( Dissous et al, 2007, 2014a; Dissous and Grevelding, 2011; Beckmann et al, 2012 ).…”

Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib

“…After perfusion, adult schistosomes were washed three times with M199 medium before being cultured in the same medium (Gibco; including glucose, sodium bicarbonate, 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid) supplemented with an antibiotic/antimycotic mixture (1%, Sigma) and new born calf serum (NCS) (10%, Sigma Aldrich) at 37°C and 5% CO 2 as described before ( Beckmann and Grevelding, 2010; Beckmann et al, 2012 ). For each experiment, 5–10 S. mansoni couples were kept per well in 6-well or 12-well plates with 2–3 ml culture medium per well.…”