P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: Prospects for reversing transport-dependent anthelmintic resistance

Abstract

Parasitic helminths cause significant disease in animals and humans. In the absence of alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides (MLs), such as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans. Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance. Multidrug resistance (MDR) ABC transporters have been implicated in ML resistance and contribute to resistance to a number of other anthelmintics. MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target. Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this needs to be balanced against possible increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance. Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination. Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread.

IDENTIFICATION OF FUNCTIONAL SNPs OF MDR1 GENE AMONG NEPHROTIC SYNDROME CHILDREN IN SOUTH INDIA

“…The gene which encodes for a transmembrane P-glycoprotein (P-gp), with 170 kD belonging to the superfamily of ATP-binding cassette (ABC) transporters that play an important role in controlling drug uptake and excretion [6,7]. P-gp is essential for many cellular processes that require the transport of substrates across cell membranes [8]. In lymphocytes, the MDR-1 gene expression has been negatively correlated with the response to the drugs of prednisone, cyclophosphamide, and cyclosporine A among NS children [9].…”

Synergism between ivermectin and the tyrosine kinase/ P -glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

“…The data described above add to the body of literature indicating that P-gps play a role in the sensitivity of nematode larvae to anthelmintics, particularly MLs (reviewed by Lespine et al, 2012), while the life-stage-dependant patterns of synergism across the two assays has allowed us to make suggestions as to the relative role of P-gps in IVM resistance in WAL larvae at different larval life stages. The second aspect of this study was to assess the potential for the use of crizotinib to reverse IVM resistance.…”

“…There are, however, significant barriers to such an approach. Most importantly, there is potential for toxic sideeffects in the host as a result of inhibiting host animal ABC transporters alongside the nematode transporters (Lespine et al, 2012) Secondly, the cost of such drugs is currently prohibitive. Such combination therapies will not be a cost-effective option while cheaper drugs remain effective, however, such cost constraints may diminish in the future as multidrug resistance becomes more intense and widespread.…”

“…Given the time and cost of developing new drugs (Woods and Williams, 2007), there is a need to manage the use of the existing drugs to preserve their usefulness for as long as possible. Means to achieve this include the elucidation of resistance mechanisms in order to develop resistance diagnostics (Kotze et al, 2014), as well as the use of compounds that can act to inhibit resistance mechanisms, and hence restore anthelmintic susceptibility to resistant worms (for example Lespine et al, 2012).…”

“…ATP binding cassette (ABC) transporters are a superfamily of transmembrane proteins which mediate the ATP-dependent efflux of a wide range of structurally and mechanistically unrelated compounds including various anticancer and anthelmintic drugs (Gottesman and Pastan, 1993;Lespine et al, 2012). Multiple ABC transporter genes have been reported in free-living and parasitic nematodes (Sheps et al, 2004;Ardelli et al, 2010;Laing et al, 2013).…”