Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chloroquine (CQ)-resistant (CQR) Plasmodium falciparum malaria parasites show a strong decrease in CQ accumulation in comparison with chloroquine-sensitive parasites. Controversy exists over the role of the plasmodial pfmdr1 gene in the CQR phenotype. pfmdr1 is a member of the superfamily of ATP-binding cassette transporters. Other members of this family are the mammalian multidrug resistance genes and the CFTR gene. We have expressed the pfmdr1-encoded protein, Pgh1, in CHO cells and Xenopus oocytes. CHO cells expressing the Pgh1 protein demonstrated an increased, verapamil-insensitive susceptibility to CQ. Conversely, no increase in drug susceptibility to primaquine, quinine, adriamycin, or colchicine was observed in Pgh1-expressing cells. CQ uptake experiments revealed an increased, ATP-dependent accumulation of CQ in Pgh1-expressing cells over the level in nonexpressing control cells. The increased CQ accumulation in Pgh1-expressing cells coincided with an enhanced in vivo inhibition of lysosomal alpha-galactosidase by CQ. CHO cells expressing Pgh1 carrying two of the CQR-associated Pgh1 amino acid changes (S1034C and N1042D) did not display an increased CQ sensitivity. Immunofluorescence experiments revealed an intracellular localization of both mutant and wild-type forms of Pgh1. We conclude from our results that wild-type Pgh1 protein can mediate an increased intracellular accumulation of CQ and that this function is impaired in CQR-associated mutant forms of the protein. We speculate that the Pgh1 protein plays an important role in CQ import in CQ-sensitive malaria parasites.
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PMID:Expression of the plasmodial pfmdr1 gene in mammalian cells is associated with increased susceptibility to chloroquine. 751 Dec 6

Since the discovery of the chloroquine (CQ) resistance reversal properties of several different, structurally unrelated classes of compounds, including antidepressants, the way is again open to employ the aminoquinoline drugs to combat malaria effectively. In this study, CQ sensitivity was restored to varying extents in vitro in the CQ-resistant Plasmodium falciparum strain RSA11 by using the antidepressants amitriptyline, citalopram, oxaprotiline, and nomifensine. The 50% inhibitory concentrations (IC(50)) of CQ were reduced from 360 to as low as 11 nM when antidepressants were present. These particular antidepressants are highly specific for blocking the ATP-binding cassette transport protein-mediated reuptake of different neurotransmitters at the synaptic level. This study was aimed at determining the extent to which the neurotransmitter reuptake-blocking properties of these antidepressants play a role in the reversal process. None of the compounds or CQ-antidepressant combinations tested had innate antimalarial activity. No chemosensitizer or combination showed an increased CQ accumulation or significant shift in the IC(50) in the CQ-sensitive clone D10. Of the compounds tested, citalopram, a highly specific serotonin reuptake blocker, produced the largest shift observed in the IC(50) for the resistant isolate RSA11. No particular class of antidepressant was found to be better than any other at restoring CQ sensitivity. We conclude that the resistance-reversing properties of these compounds do not correlate with their activities as reuptake blockers.
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PMID:Role of the neurotransmitter reuptake-blocking activity of antidepressants in reversing chloroquine resistance in vitro in Plasmodium falciparum. 1099 45

The elucidation of the molecular details of drug resistance phenomena is a very active area of research that crosses many disciplinary boundaries. Drug resistance is due to altered drug-target interaction, and/or dysregulated signaling related to cell growth and death. Since many drugs need to rapidly diffuse into and within cells in order to find their targets, and since transmembrane ion transport is an important facet of cellular signaling, it is not surprising that membrane transport phenomena have been implicated in the evolution of drug resistance in tumor cells, bacteria, and intracellular parasites such as Plasmodium falciparum, the causative agent of the most lethal form of human malaria. The most infamous membrane transport protein involved in drug resistance is "MDR protein" or "P-glycoprotein" (Pgp),1 which was found to be overexpressed in drug-resistant tumor cells over 15 years ago, and which is representative of the ATP-binding cassette (ABC) superfamily that also includes the important cystic fibrosis transmembrane conductance regulator (CFTR) and sulfonyl urea receptor (SUR) ion channels. Availability of mouse and human Pgp cDNA rather quickly led to the identification of homologues in many species, including P. falciparum, and these were de facto assumed to be the ultimate determinants of drug resistance in these systems as well. However, research over the past 10 years has taught us that this assumption likely is wrong and that the situation is more complex. We now know that human Pgp plays a relatively minor role in clinically relevant tumor drug resistance, and that an integral membrane protein with no homology to the ABC superfamily, Pfcrt, ultimately confers chloroquine resistance in P. falciparum. Thus, the general hypothesis that membrane transport and membrane transport proteins are important in drug resistance phenomena remains correct, but at a genetic, biochemical, and physiological level we have recently witnessed a few very interesting surprises.
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PMID:A novel transporter, Pfcrt, confers antimalarial drug resistance. 1242 67

Leishmaniasis is the most important emerging and uncontrolled infectious disease and the second cause of death among parasitic diseases, after Malaria. One of the main problems concerning the control of infectious diseases is the increased resistance to usual drugs. Overexpression of P-glycoprotein (Pgp)-like transporters represents a very efficient mechanism to reduce the intracellular accumulation of drugs in cancer cells and parasitic protozoans, thus conferring a multidrug resistance (MDR) phenotype. Pgps are active pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. The inhibition of the activity of these proteins represents an interesting way to control drug resistance both in cancer and in infectious diseases. Most conventional mammalian Pgp-MDR modulators are ineffective in the modulation of Pgp activity in the protozoan parasite Leishmania. Consequently, there is a necessity to find effective modulators of Pgp-MDR for protozoan parasites. In this review we describe a rational strategy developed to find specific Pgp-MDR modulators in Leishmania, using natural and semisynthetic dihydro-beta-agarofuran sesquiterpenes from Celastraceae plants. A series of these compounds have been tested on a MDR Leishmania tropica line overexpressing a Pgp transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. Almost all of these natural compounds showed potent reversal activity with different degrees of selectivity and a significant low toxicity. The three-dimensional quantitative structure-activity relationship using the comparative molecular similarity indices analysis (CoMSIA), was employed to characterize the requirements of these sesquiterpenes as modulators at Pgp-like transporter in Leishmania.
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PMID:Dihydro-beta-agarofuran sesquiterpenes: a new class of reversal agents of the multidrug resistance phenotype mediated by P-glycoprotein in the protozoan parasite Leishmania. 1617 49

ATP-binding cassette transporters play an important role in drug resistance and nutrient transport. In the human malaria parasite Plasmodium falciparum, a homolog of the human p-glycoprotein (PfPgh-1) was shown to be involved in resistance to several drugs. More recently, many transporters were associated with higher IC(50) levels in responses to chloroquine (CQ) and quinine (QN) in field isolates. Subsequent studies, however, could not confirm the associations, although inaccuracy in drug tests in the later studies could contribute to the lack of associations. Here we disrupted a gene encoding a putative multidrug resistance-associated protein (PfMRP) that was previously shown to be associated with P. falciparum responses to CQ and QN. Parasites with disrupted PfMRP (W2/MRPDelta) could not grow to a parasitemia higher than 5% under normal culture conditions, possibly because of lower efficiency in removing toxic metabolites. The W2/MRPDelta parasite also accumulated more radioactive glutathione, CQ, and QN and became more sensitive to multiple antimalarial drugs, including CQ, QN, artemisinin, piperaquine, and primaquine. PfMRP was localized on the parasite surface membrane, within membrane-bound vesicles, and along the straight side of the D-shaped stage II gametocytes. The results suggest that PfMRP plays a role in the efflux of glutathione, CQ, and QN and contributes to parasite responses to multiple antimalarial drugs, possibly by pumping drugs outside the parasite.
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PMID:Disruption of a Plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione. 1911 44

Expanding drug resistance could become a major problem in malaria treatment, as only a limited number of effective antimalarials are available. Drug resistance has been associated with single nucleotide polymorphisms and an increased copy number of multidrug resistance protein 1 (MDR1), an ATP-binding cassette (ABC) protein family member. Many ABC transport proteins are membrane transporters that actively translocate a wide range of structurally and functionally diverse amphipathic compounds. The Plasmodium falciparum ABC family consists of 16 members and current knowledge of their physiological function and contribution to antimalarial drug resistance is limited. Here, we give an overview of the Plasmodium ABC family members with reference to their possible role in multidrug resistance.
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PMID:The ABCs of multidrug resistance in malaria. 2054 73

Malaria is a deadly infectious disease in many tropical and subtropical countries. Previous efforts to eradicate malaria have failed, largely due to the emergence of drug-resistant parasites, insecticide-resistant mosquitoes and, in particular, the lack of drugs or vaccines to block parasite transmission. ATP-binding cassette (ABC) transporters are known to play a role in drug transport, metabolism, and resistance in many organisms, including malaria parasites. To investigate whether a Plasmodium falciparum ABC transporter (Pf14_0244 or PfABCG2) modulates parasite susceptibility to chemical compounds or plays a role in drug resistance, we disrupted the gene encoding PfABCG2, screened the recombinant and the wild-type 3D7 parasites against a library containing 2,816 drugs approved for human or animal use, and identified an antihistamine (ketotifen) that became less active against the PfABCG2-disrupted parasite in culture. In addition to some activity against asexual stages and gametocytes, ketotifen was highly potent in blocking oocyst development of P. falciparum and the rodent parasite Plasmodium yoelii in mosquitoes. Tests of structurally related tricyclic compounds identified additional compounds with similar activities in inhibiting transmission. Additionally, ketotifen appeared to have some activity against relapse of Plasmodium cynomolgi infection in rhesus monkeys. Further clinical evaluation of ketotifen and related compounds, including synthetic new derivatives, in blocking malaria transmission may provide new weapons for the current effort of malaria eradication.
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PMID:A class of tricyclic compounds blocking malaria parasite oocyst development and transmission. 2312 54

Members of the ATP-binding cassette (ABC)-type transporter superfamily have been implicated in multidrug resistance in malaria, and various mechanistic models have been postulated to explain their interaction with diverse antimalarial drugs. To gain insight into the pharmacological benefits of inhibiting ABC-type transporters in malaria chemotherapy, we investigated the in vitro chemosensitization potential of various P-glycoprotein inhibitors. A fluorescent chloroquine derivative was synthesized and used to assess the efflux dynamics of chloroquine in MDR and wild type Plasmodium falciparum parasites. This novel BODIPY-based probe accumulated in the digestive vacuole (DV) of CQ-sensitive parasites but less so in MDR cells. Pre-exposure of the MDR parasites to non-cytocidal concentrations of unlabeled chloroquine resulted in a diffused cytoplasmic retention of the probe whereas a similar treatment with the CQR-reversing agent, chlorpheniramine, resulted in DV accumulation. A diffused cytoplasmic distribution of the probe was also obtained following treatment with the P-gp specific inhibitors zosuquidar and tariquidar, whereas treatments with the tyrosine kinase inhibitors gefitinib or imatinib produced a partial accumulation within the DV. Isobologram analyses of the interactions between these inhibitors and the antimalarial drugs chloroquine, mefloquine, and artemisinin revealed distinct patterns of drug synergism, additivity and antagonism. Taken together, the data indicate that competitive tyrosine kinase and noncompetitive P-glycoprotein ATPase-specific inhibitors represent two new classes of chemosensitizing agents in malaria parasites, but caution against the indiscriminate use of these agents in antimalarial drug combinations.
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PMID:Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites. 2354 83

Drug resistance in Plasmodium falciparum remains a challenge for the malaria eradication programmes around the world. With the emergence of artemisinin resistance, the efficacy of the partner drugs in the artemisinin combination therapies (ACT) that include quinoline-based drugs is becoming critical. So far only few resistance markers have been identified from which only two transmembrane transporters namely PfMDR1 (an ATP-binding cassette transporter) and PfCRT (a drug-metabolite transporter) have been experimentally verified. Another P. falciparum transporter, the ATP-binding cassette containing multidrug resistance-associated protein (PfMRP2) represents an additional possible factor of drug resistance in P. falciparum. In this study, we identified a parasite clone that is derived from the 3D7 P. falciparum strain and shows increased resistance to chloroquine, mefloquine and quinine through the trophozoite and schizont stages. We demonstrate that the resistance phenotype is caused by a 4.1 kb deletion in the 5' upstream region of the pfmrp2 gene that leads to an alteration in the pfmrp2 transcription and thus increased level of PfMRP2 protein. These results also suggest the importance of putative promoter elements in regulation of gene expression during the P. falciparum intra-erythrocytic developmental cycle and the potential of genetic polymorphisms within these regions to underlie drug resistance.
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PMID:Structural polymorphism in the promoter of pfmrp2 confers Plasmodium falciparum tolerance to quinoline drugs. 2437 51

ATP-binding cassette (ABC) transporters serve a variety of physiological functions as well as play key roles in drug resistance. The genome of the human malaria parasite, Plasmodium falciparum, encodes multiple members of this family, one of which, gABCG2, is transcribed predominantly in the gametocyte stage. Here we use gene deletion and tagging to investigate the expression, localization and function of gABCG2. The protein is found in a single dot-like lipid-rich structure within female, but not male, gametocytes. gABCG2-knockout cell lines produce more gametocytes of both sexes. By contrast, cholesteryl esters, diacylglycerols and triacylglycerols are significantly reduced in gABCG2-knockout gametocyte stages. We propose a role for gABCG2 in the regulation of gametocyte numbers and in the accumulation of neutral lipids, which are likely important for parasite development in the insect stages of the parasite life cycle.
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PMID:A female gametocyte-specific ABC transporter plays a role in lipid metabolism in the malaria parasite. 2519 3


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