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

Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance; Pgh1 has also been implicated in resistance to mefloquine and halofantrine. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.
 ...
PMID:Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. 1070 90

Cryptotanshinone (1), a quinoid diterpene with a nor-abietane skeleton, and three new natural products, 1beta-hydroxycryptotanshinone (2), 1-oxocryptotanshinone (3), and 1-oxomiltirone (4), were isolated from roots of the Iranian medicinal plant Perovskia abrotanoides. Their structures were established using homo- and heteronuclear two-dimensional NMR experiments, supported by HRMS. The total amount of tanshinones isolated from dry roots of Perovskia abrotanoides was about 1.5%. The compounds exhibited leishmanicidal activity in vitro (IC(50) values in the range 18-47 microM). These findings provide a rationale for traditional use of the roots in Iran as a constituent of poultices for treatment of cutaneous leishmaniasis. The isolated tanshinones also inhibited growth of cultured malaria parasites (3D7 strain of Plasmodium falciparum), drug-sensitive KB-3-1 human carcinoma cell line, multidrug-resistant KB-V1 cell line, and human lymphocytes activated with phytohaemagglutinin A (IC(50) values in the range 5-45 microM). The toxicity of tanshinones toward the drug-sensitive KB-3-1 and the multidrug-resistant KB-V1 cells was the same, indicating that the compounds are not substrates for the P-glycoprotein drug efflux pump.
 ...
PMID:Leishmanicidal, antiplasmodial, and cytotoxic activity of novel diterpenoid 1,2-quinones from Perovskia abrotanoides: new source of tanshinones. 1172 May 20

Genetic and biochemical approaches to studies of drug resistance mechanisms in Plasmodium falciparum have raised controversies and contradictions over the past several years. A different and novel chemical approach to this important problem is desirable at this point in time. Recently, the molecular basis of drug resistance in P. falciparum has been associated with mutations in the resistance genes, Chloroquine Resistance Transporter (PfCRT) and the P-glycoprotein homologue (Pgh1). Although not the determinant of chloroquine resistance in P. falciparum, mutations in Pgh1 have important implications for resistance to other antimalarial drugs. Because it is mutations in the aforementioned resistance genes rather than overexpression that has been associated with drug resistance in malaria, studies on mechanisms of drug resistance and its reversal by chemosensitisers should benefit from a chemical approach. Target-oriented organic synthesis of chemosensitisers against proteins implicated in drug resistance in malaria should shed light on mechanism of drug resistance and its reversal in this area. The effect of structurally diverse chemosensitisers should be examined on several putative resistance genes in P. falciparum to deal with antimalarial drug resistance in the broadest sense. Therefore, generating random mutations of these resistance proteins and subsequent screening in search of a specific phenotype followed by a search for mutations and/or chemosensitisers that affect a specific drug resistance pathway might be a viable strategy. This diversity-oriented organic synthesis approach should offer the means to simultaneously identify resistance proteins that can serve as targets for therapeutic intervention (therapeutic target validation) and chemosensitisers that modulate the functions of these proteins (chemical target validation).
 ...
PMID:A chemical approach towards understanding the mechanism and reversal of drug resistance in Plasmodium falciparum: is it viable? 1212 Oct 4

Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 micro M verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.
 ...
PMID:Reversal of mefloquine and quinine resistance in Plasmodium falciparum with NP30. 1287 95

Mutations and/or overexpression of various transporters are known to confer drug resistance in a variety of organisms. In the malaria parasite Plasmodium falciparum, a homologue of P-glycoprotein, PfMDR1, has been implicated in responses to chloroquine (CQ), quinine (QN) and other drugs, and a putative transporter, PfCRT, was recently demonstrated to be the key molecule in CQ resistance. However, other unknown molecules are probably involved, as different parasite clones carrying the same pfcrt and pfmdr1 alleles show a wide range of quantitative responses to CQ and QN. Such molecules may contribute to increasing incidences of QN treatment failure, the molecular basis of which is not understood. To identify additional genes involved in parasite CQ and QN responses, we assayed the in vitro susceptibilities of 97 culture-adapted cloned isolates to CQ and QN and searched for single nucleotide polymorphisms (SNPs) in DNA encoding 49 putative transporters (total 113 kb) and in 39 housekeeping genes that acted as negative controls. SNPs in 11 of the putative transporter genes, including pfcrt and pfmdr1, showed significant associations with decreased sensitivity to CQ and/or QN in P. falciparum. Significant linkage disequilibria within and between these genes were also detected, suggesting interactions among the transporter genes. This study provides specific leads for better understanding of complex drug resistances in malaria parasites.
 ...
PMID:Multiple transporters associated with malaria parasite responses to chloroquine and quinine. 1289 22

One of the major mechanisms of multidrug resistance (MDR) in cancer therapy is the overexpression of P-glycoprotein (Pgp). We previously reported that pyronaridine (PND), a synthetic quinoline derivative in the clinic for the treatment of malaria infections, was capable of reversing MDR phenotype in Pgp-overexpressing tumor cells. Here we further evaluated the reversal activity of PND using two Pgp-overexpressing human tumor cell lines: K562/A02 and MCF-7/ADR. PND significantly enhanced the sensitivity of K562/A02 and MCF-7/ADR cells to doxorubicin (DOX), but had no such effect on the parent K562 and MCF-7 cells. The MDR-modulating effect of PND persisted for longer than 24h after removal of the agent from the culture. In nude mice bearing K562/A02 xenografts PND significantly enhanced the antitumor activity of DOX when given intraperitoneally or orally without increasing the toxicity of DOX. Our observations suggest that PND represents a promising agent for overcoming MDR in cancer therapy.
 ...
PMID:Pyronaridine, a novel modulator of P-glycoprotein-mediated multidrug resistance in tumor cells in vitro and in vivo. 1519 84

Chloroquine has been the mainstay of antimalarial chemotherapy but the rapid spread of resistance to this important drug has now compromised its efficacy. The mechanism of chloroquine resistance has not been known but recent evidence from Plasmodium falciparum, the causative agent of the most severe form of human malaria, suggested similarities to the multidrug resistance phenotype (MDR) of mammalian tumour cells which is mediated by a protein molecule termed P-glycoprotein. Two mdr genes (pfmdr1 and pfmdr2) encoding P-glycoprotein homologues have been identified in P. falciparum and one of these (pfmdr1) has several alleles that have been linked to the chloroquine resistance phenotype. In contrast analysis of a genetic cross between chloroquine-resistant and -sensitive P. falciparum has suggested that the genes encoding the known P-glycoprotein homologues are not linked. This review outlines the similarities of the chloroquine resistance phenotype with the MDR phenotype of mammalian tumour cells and explores the possible role of the pfmdr genes.
 ...
PMID:The P-glycoprotein homologues of Plasmodium falciparum: Are they involved in chloroquine resistance? 1546 47

Chloroquine (CQ)-resistant Plasmodium falciparum appears to decrease CQ accumulation in its food vacuole by enhancing its efflux via an active membrane pump, which has been reported to be a P-glycoprotein-like transporter. Rifampicin (RIF) is a P-glycoprotein inhibitor and also has some antimalarial activity. It is hoped that a combination of choloroquine-rifampicin (CQ + RIF) would be advantageous in the treatment of CQ-resistant malaria. Swiss albino mice were inoculated with CQ-resistant P. berghei intraperitoneally, and studied for the effect of CQ versus the combination of CQ + RIF at various doses on the clearance of parasitemia, the survival of the mice, and the recrudescence of malaria. Paradoxically, RIF decreased the survival rate and rate of clearance of parasitemia and increased the rate of recrudescence significantly when combined with various doses of CQ. Our results indicated that RIF worsened the course of the disease, and we concluded that RIF should not be combined with CQ in the treatment of malaria.
 ...
PMID:Rifampicin antagonizes the effect of choloroquine on chloroquine-resistant Plasmodium berghei in mice. 1550 75

The ATPase activity of the human malaria parasite, Plasmodium falciparum was investigated using two experimental systems, (i) digestive vacuoles, and (ii) purified plasma membranes isolated from a chloroquine-sensitive and a chloroquine-resistant strain. No correlation between the level of ATPase activity and chloroquine sensitivity could be detected. In both systems, the ATPase activity of the chloroquine-resistant and -sensitive strain was decreased in the presence of the P-glycoprotein inhibitor vanadate. Susceptibility to inhibition by vanadate together with the lack of effect of ouabain implies a P-type ATPase activity in the plasma membrane. Furthermore, the inhibition of Fac8 ATPase activity by oligomycin both in the digestive vacuoles and the plasma membranes would be consistent with higher levels of Pgh1 in Fac8. Our data are consistent with the presence of a V-type H+-ATPase in the parasite food vacuole. Bafilomycin A1 and N-ethylmaleimide decreased the vacuolar ATPase activity in both chloroquine-resistant and -sensitive strains. Interestingly, a 30% decrease was observed between the ATPase activity of plasma membranes isolated from Fac8 and D10 in the presence of bafilomycin A1, suggesting the presence of a V-type ATPase in D10 plasma membrane that is underexpressed or altered in the plasma membrane of the chloroquine-resistant Fac8. The chemosensitisers tested had no effect on the ATPase activity of chloroquine-resistant P. falciparum in both systems suggesting that their activity is not mediated through an ATP-dependent mechanism. No effect was observed on the vacuolar ATPase activity in the presence of the antimalarials tested indicating that an ATP-dependent transport has not been activated.
 ...
PMID:ATPase activity of purified plasma membranes and digestive vacuoles from Plasmodium falciparum. 1581 26

The emergence of drug-resistance poses a major obstacle to the control of malaria. A homolog of the major multidrug-transporter in mammalian cells was identified, Plasmodium falciparum multidrug resistance protein-1, pfmdr1, also known as the P-glycoprotein homolog 1, Pgh-1. Several studies have demonstrated strong, although incomplete, associations between resistance to the widely used antimalarial drug chloroquine and mutation of the pfmdr1 gene in both laboratory and field isolates. Genetic studies have confirmed a link between mutation of the pfmdr1 gene and chloroquine-resistance. Although not essential for chloroquine-resistance, pfmdr1 plays a role in modulating levels of resistance. At the same time it appears to be a significant component in resistance to the structurally related drug quinine. A strong association has been observed between possession of the wildtype form of pfmdr1, amplification of pfmdr1 and resistance to hydrophobic drugs such as the arylaminoalcohol mefloquine and the endoperoxide artemisinin derivatives in field isolates. This is supported by genetic studies. The arylaminoalcohol and endoperoxide drugs are structurally unrelated drugs and this resistance resembles true multidrug resistance. Polymorphism in pfmdr1 and gene amplification has been observed throughout the world and their usefulness in predicting resistance levels is influenced by the history of drug selection of each population.
 ...
PMID:Contribution of the pfmdr1 gene to antimalarial drug-resistance. 1587 20


<< Previous 1 2 3 4 5 Next >>