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José M. Pérez-Victoria

Bio: José M. Pérez-Victoria is an academic researcher from Spanish National Research Council. The author has contributed to research in topics: ATP-binding cassette transporter & Leishmania. The author has an hindex of 24, co-authored 41 publications receiving 1858 citations.

Papers
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Journal ArticleDOI
TL;DR: This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found and constitute promising potentialmodulators of multidrug resistance.
Abstract: Cancer cell resistance to chemotherapy is often mediated by overexpression of P-glycoprotein, a plasma membrane ABC (ATP-binding cassette) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. P-glycoprotein (ABCB1, according to the human gene nomenclature committee) consists of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)2 domain topology. Homologous ABC multidrug transporters, from the same ABCB family, are found in many species such as Plasmodium falciparum and Leishmania spp. protozoa, where they induce resistance to antiparasitic drugs. In yeasts, some ABC transporters involved in resistance to fungicides, such as Saccharomyces cerevisiae Pdr5p and Snq2p, display a different (NBD-TMD)2 domain topology and are classified in another family, ABCG. Much effort has been spent to modulate multidrug resistance in the different species by using specific inhibitors, but generally with little success due to additional cellular targets and/or extrusion of the potential inhibitors. This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found. An in vitro 'rational screening' was performed among the large flavonoid family using a four-step procedure: (i) direct binding to purified recombinant cytosolic NBD and/or full-length transporter, (ii) inhibition of ATP hydrolysis and energy-dependent drug interaction with transporter-enriched membranes, (iii) inhibition of cell transporter activity monitored by flow cytometry and (iv) chemosensitization of cell growth. The results indicate that prenylated flavonoids bind with high affinity, and strongly inhibit drug interaction and nucleotide hydrolysis. As such, they constitute promising potential modulators of multidrug resistance.

237 citations

Journal ArticleDOI
TL;DR: 6-Prenylchrysin and tectochrysin constitute new and promising inhibitors for the reversal of ABCG2-mediated drug transport.
Abstract: Overexpression of breast cancer resistance protein ABCG2 confers multidrug resistance in cancer cells. The GF120918-sensitive drug efflux activity of human wild-type (R482) ABCG2-transfected cells was used for rational screening of inhibitory flavonoids and establishment of structure-activity relationships. Flavones were found more efficient than flavonols, isoflavones, and flavanones. Differentially substituted flavone derivatives indicated positive OH effects at position 5, in contrast to positions 3 and 7. A methoxy at position 7 was slightly positive in tectochrysin, whereas a strong positive effect was produced by prenylation at position 6. The potency of 6-prenylchrysin was comparable with that of GF120918 (IC50 = 0.3 micromol/L). Both 6-prenylchrysin and tectochrysin seemed specific for ABCG2 because no interaction was detected with either P-glycoprotein or MRP1. The ABCG2 resistance profile in vitro is altered by mutation at amino acid 482. The R482T mutation limited the effect of prenylation on ABCG2 inhibition. Whereas GF120918 strongly inhibited the ATPase activity of wild-type ABCG2, neither 6-prenylchrysin nor tectochrysin altered the activity. In contrast, all three inhibitors stimulated the ATPase activity of mutant ABCG2. 6-Prenylchrysin at 0.5 micromol/L efficiently sensitized the growth of wild-type ABCG2-transfected cells to mitoxantrone, whereas higher concentrations were required for the mutant ones. In contrast, 1 micromol/L tectochrysin was sufficient to fully sensitize mutant ABCG2-transfected cells, whereas higher concentrations were required for the wild-type ones. Both flavones exhibited a lower intrinsic cytotoxicity than GF120918 and were apparently not transported by ABCG2. 6-Prenylchrysin and tectochrysin therefore constitute new and promising inhibitors for the reversal of ABCG2-mediated drug transport.

174 citations

Journal ArticleDOI
TL;DR: The involvement of a member of the ATP-binding cassette (ABC) superfamily, the LeishmaniaP-glycoprotein-like transporter, in resistance to drugs used in the treatment of leishmaniasis supports the importance of developing new specific inhibitors of this ABC transporter.
Abstract: Drug resistance has emerged as a major impediment in the treatment of leishmaniasis. Alkyl-lysophospholipids (ALP), originally developed as anticancer drugs, are considered to be the most promising antileishmanial agents. In order to anticipate probable clinical failure in the near future, we have investigated possible mechanisms of resistance to these drugs in Leishmania spp. The results presented here support the involvement of a member of the ATP-binding cassette (ABC) superfamily, the Leishmania P-glycoprotein-like transporter, in the resistance to ALP. (i) First, a multidrug resistance (MDR) Leishmania tropica line overexpressing a P-glycoprotein-like transporter displays significant cross-resistance to the ALP miltefosine and edelfosine, with resistant indices of 9.2- and 7.1-fold, respectively. (ii) Reduced expression of P-glycoprotein in the MDR line correlates with a significant decrease in ALP resistance. (iii) The ALP were able to modulate the P-glycoprotein-mediated resistance to daunomycin in the MDR line. (iv) We have found a new inhibitor of this transporter, the sesquiterpene C-3, that completely sensitizes MDR parasites to ALP. (v) Finally, the MDR line exhibits a lower accumulation than the wild-type line of bodipy-C5-PC, a fluorescent analogue of phosphatidylcholine that has a structure resembling that of edelfosine. Also, C-3 significantly increases the accumulation of the fluorescent analogue to levels similar to those of wild-type parasites. The involvement of the Leishmania P-glycoprotein-like transporter in resistance to drugs used in the treatment of leishmaniasis also supports the importance of developing new specific inhibitors of this ABC transporter.

122 citations

Journal ArticleDOI
TL;DR: Results suggest that LiABCG6 could be implicated in phospholipid trafficking and drug resistance in Leishmania protozoan parasites.
Abstract: Leishmaniasis treatment is hampered by the increased appearance of treatment failure. ATP-binding cassette (ABC) transporters are usually involved in drug resistance both in tumor cells and in microorganisms. Here we report the characterization of an ABCG-like transporter, LiABCG6, localized mainly at the plasma membrane in Leishmania protozoan parasites. When overexpressed, this half-transporter confers significant resistance to the leishmanicidal agents miltefosine and sitamaquine. This resistance phenotype is mediated by a reduction in intracellular drug accumulation. LiABCG6 also reduces the accumulation of short-chain fluorescent phospholipid analogues of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. As a whole, these results suggest that LiABCG6 could be implicated in phospholipid trafficking and drug resistance.

89 citations

Journal ArticleDOI
TL;DR: This review summarizes the known classes of inhibitors that are either specific for BCRP or also inhibit the other multidrug resistance ABC transporters.
Abstract: Breast cancer resistance protein (BCRP/ABCG2) belongs to the ATP-binding cassette (ABC) transporter superfamily. It is able to efflux a broad range of anti-cancer drugs through the cellular membrane, thus limiting their anti-proliferative effects. Due to its relatively recent discovery in 1998, and in contrast to the other ABC transporters P-glycoprotein (MDR1/ABCB1) and multidrug resistance-associated protein (MRP1/ABCC1), only a few BCRP inhibitors have been reported. This review summarizes the known classes of inhibitors that are either specific for BCRP or also inhibit the other multidrug resistance ABC transporters. Information is presented on structure-activity relationship aspects and how modulators may interact with BCRP.

87 citations


Cited by
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Journal ArticleDOI
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Abstract: Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

2,620 citations

Journal ArticleDOI
TL;DR: Flavonoids are plant pigments that are synthesised from phenylalanine, generally display marvelous colors known from flower petals, mostly emit brilliant fluorescence when they are excited by UV light, and are ubiquitous to green plant cells.

2,424 citations

Journal ArticleDOI
TL;DR: It is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.
Abstract: Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

1,450 citations

Journal ArticleDOI
TL;DR: The role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed and species variations in substrate specificity and tissue distribution of these transporters are addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.

1,327 citations

Journal ArticleDOI
Wenying Ren1, Zhenhua Qiao1, Hong-wei Wang1, Lei Zhu1, Li Zhang1 
TL;DR: Results from laboratory studies, epidemiological investigations, and human clinical trials indicate that flavonoids have important effects on cancer chemoprevention and chemotherapy.
Abstract: Flavonoids are polyphenolic compounds that are ubiquitously in plants. They have been shown to possess a variety of biological activities at nontoxic concentrations in organisms. The role of dietary flavonoids in cancer prevention is widely discussed. Compelling data from laboratory studies, epidemiological investigations, and human clinical trials indicate that flavonoids have important effects on cancer chemoprevention and chemotherapy. Many mechanisms of action have been identified, including carcinogen inactivation, antiproliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, antioxidation and reversal of multidrug resistance or a combination of these mechanisms. Based on these results, flavonoids may be promising anticancer agents.

1,005 citations