Relevance of the chemical charge of rhodamine dyes to multiple drug resistance

Lampidis, Théodore J.; Castello, Carlos; Giglio, Auro del; Pressman, Berton C.; Viallet, Pierre; Trevorrow, Kenneth W.; Valet, G.; Tapiero, Haïm; Savaraj, Niramol

doi:10.1016/0006-2952(89)90525-x

Cited by 69 publications

(39 citation statements)

References 7 publications

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“…Our results suggest that either an analogous drug accumulation differential does not exist for the rhodamines in the D6 and W2 clones of P. falciparum or, if it does, the parasite is more susceptible to rhodamine B than to rhodamines 123 and 6G. We can also infer that drug resistance in P. falciparum does not depend on the net charge of the rhodamine dye, as it does in mammalian cells (34), because both rhodamine B and 6G were nearly equipotent against both the D6 and the W2 clones.…”

Section: Discussionmentioning

confidence: 63%

Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines

Vennerstrom

Makler

Angerhofer

et al. 1995

Antimicrob Agents Chemother

204

129

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In 1891 Guttmann and Ehrlich (P. Guttmann and P. Ehrlich, Berlin Klin. Wochenschr. 28:953-956, 1891) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. Since that time, sporadic reports of the antimalarial properties of several xanthene and azine dyes related to methylene blue have been noted. We report here the results from a reexamination of the antimalarial properties of methylene blue, Janus green B, and three rhodamine dyes and disclose new antimalarial data for 16 commercially available structural analogs of these dyes. The 50% inhibitory concentrations for the chloroquinesusceptible D6 clone and SN isolate and the chloroquine-resistant W2 clone of Plasmodium falciparum were determined by the recently described parasite lactate dehydrogenase enzyme assay. No cross-resistance to chloroquine was observed for any of the dyes. For the 21 dyes tested, no correlation was observed between antimalarial activity and cytotoxicity against KB cells. No correlation between log P (where P is the octanol/ water partition coefficient) or relative catalyst efficiency for glucose oxidation and antimalarial activity or cytotoxicity was observed for the dyes as a whole or for the thiazine dyes. The thiazine dyes were the most uniformly potent structural class tested, and among the dyes in this class, methylene blue was notable for both its high antimalarial potency and selectivity.In 1891 Guttmann and Ehrlich (25) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. The only side effect that they noted was a ''spastic irritation of the bladder,'' which was partially alleviated by the administration of powdered nutmeg. They selected methylene blue because it had been previously demonstrated by Celli and Guarnieri to specifically stain plasmodia (25) and also because Ehrlich and Leppmann had prior experience in the therapeutic use of this dye in the successful clinical treatment of neuralgias (32). Guttmann and Ehrlich (25) apparently made no further attempt to pursue this interesting observation, although as late as 1956, Dale (14), in his introduction to The Collected Papers of Paul Ehrlich, noted that ''methylene blue itself has there [in the Balkan countries] retained a fairly extensive use, for the treatment of malaria in cases which have been found refractory to quinine.'' Moreover, methylene blue, along with quinine, served as structural prototypes (48) which led to the subsequent development of the 8-aminoquinoline pamaquine and the 9-aminoacridine mepacrine (quinacrine) in 1925 and 1930, respectively (Fig. 1).In the past decade, sporadic reports (7,18,19,21,27) of the antimalarial properties of several xanthene (rhodamines 123, 6G, and B) and azine (Janus green B) dyes related to methylene blue ha...

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Section: Discussionmentioning

confidence: 63%

Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines

Vennerstrom

Makler

Angerhofer

et al. 1995

Antimicrob Agents Chemother

204

129

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Section: Rntroductionmentioning

confidence: 99%

“…However, the mechanism according to which the drugs are removed from the cells is still unknown. It has been reported that (i) a wide variety of drugs recognized by P-gp are positively charged [8]; (ii) an ideal modulator of P-gp would have at least two planar aromatic rings, a tertiary nitrogen that would be charged at physiological pH, and be relatively lipophilic [9]; and (iii) P-gp specifically pumps out the protonated form of daunorubicin [lo].A better comprehension of the molecular requirements for drug-protein interactions is a necessary prerequisite to the rational design of new compounds capable of overcoming MDR. To get some insight into that problem, we have studied the uptake and the efflux in reistant cells of a neutral molecule, OH-Dox, a synthetic analog of Dox in which the amine group of the sugar portion has been replaced by a hydroxyl group (Scheme 1) [l l-l 31.…”

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confidence: 99%

P‐glycoprotein‐mediated efflux of hydroxyrubicin, a neutral anthracycline derivative, in resistant K562 cells

et al. 1994

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Hydroxyrubin (OH-Dox), a neutral doxorubicin derivative that is only slightly cross-resistant to doxorubicin (Dox), can be actively pumped out of resistant K562 cells by P-glycoprotein (P-gp). This efllux is saturable and can be inhibited by verapamil. The Michaelis constant is equal to 2 f 0.5 PM. However, the efficiency of P-gp in pumping out the drugs is 2.5 times less for OH-Dox than for Dox. This shows that in order to be pumped out by P-gp a molecule does not necessarily have to have a basic center. The mean influx coefficient for the drug is 5 times higher for OH-Dox than for Dox. In conclusion, the degree of resistance of analogs is related not only to their ability to be recognized and transported by P-gp but also, and probably essentially, to their kinetics of uptake. Both parameters have to be taken into account in the rational design of new compounds capable of overcoming multidrug resistance.Key words: Multidrug resistance; P-Glycoprotein; Doxorubicin; Michaelis constant rntroductionThe multidrug resistance (MDR) cell phenotype reflects the capacity of some cell strains to display cross-resistance to certain cytotoxic drugs (typically anthracyclines, vinca alkaloids, colchicine, etc.) [ 1,2]. It is now well established that the MDR phenotype is strongly correlated with the over-expression of P-gp, a 170-kDa membrane glycoprotein encoded by mdr class genes, that actively pumps drugs out of resistant cells. This effiux is energy dependent.It is now generally accepted that the uptake of drugs, such as anthracyclines, by cells occurs by passive diffusion of the neutral form of the drug [3-71. However, the mechanism according to which the drugs are removed from the cells is still unknown. It has been reported that (i) a wide variety of drugs recognized by P-gp are positively charged [8]; (ii) an ideal modulator of P-gp would have at least two planar aromatic rings, a tertiary nitrogen that would be charged at physiological pH, and be relatively lipophilic [9]; and (iii) P-gp specifically pumps out the protonated form of daunorubicin [lo].A better comprehension of the molecular requirements for drug-protein interactions is a necessary prerequisite to the rational design of new compounds capable of overcoming MDR. To get some insight into that problem, we have studied the uptake and the efflux in reistant cells of a neutral molecule, OH-Dox, a synthetic analog of Dox in which the amine group of the sugar portion has been replaced by a hydroxyl group (Scheme 1) [l l-l 31. At neutral pH, about 96% of the amine group of Dox is protonated and the molecule carries a net positive charge of + 1 [6]. Substitution of a hydroxyl group for the amine group results in the loss of the positive charge.We present here data that clearly demonstrate (i) the existence of P-gp-mediated efflux of the uncharged molecule (OH-Dox), and (ii) the fact that the kinetics of uptake must be taken into account when searching for new non-cross-resistant compounds. *Corresponding author. Fax: (33) (1) 48 38 77 77.Abbreviations; M...

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“…Further studies showed that the emergence of MDR was associated with increased levels of a transmembrane glycoprotein (24), P glycoprotein (P-gp). P-gp, the product of the MDR1 gene, is a 170-kDa protein that functions as an energy-dependent drug efflux pump whose substrates include naturally occurring, lipophilic agents with a complex ring structure such as Vinca alkaloids, anthracyclines, epipodophyllotoxins, and certain rhodamine dyes (18,26,37). Exposure of tumor cells to any of these substrates can generate overexpression of P-gp, resulting in the MDR phenotype.…”

mentioning

confidence: 99%

Doxycycline Induces Expression of P Glycoprotein in MCF-7 Breast Carcinoma Cells

Mealey¹,

Barhoumi

Burghardt

et al. 2002

Antimicrob Agents Chemother

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P-glycoprotein (P-gp) overexpression by tumor cells imparts resistance to multiple antineoplastic chemotherapeutic agents (multiple drug resistance). Treatment of tumor cells with chemotherapeutic agents such as anthracyclines, epipodophyllotoxins, andVinca alkaloids results in induction of P-gp expression. This study was performed to determine if clinically relevant antimicrobial drugs (i.e., drugs that are used to treat bacterial infections in cancer patients) other than antineoplastic agents can induce expression of P-gp in MCF-7 breast carcinoma cells. Expression of P-gp and MDR1 mRNA was determined in samples from MCF-7 cells that were treated in culture with doxorubicin (positive control) and the antimicrobial drugs doxycycline, piperacillin, and cefoperazone. The functional status of P-gp was assessed using laser cytometry to determine intracellular doxorubicin concentrations. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay was used to determine if the cytotoxicity of experimental drugs was related to their ability to induce P-gp expression. MCF-7 cells treated with doxycycline (MCF-7/doxy) were stimulated to overexpress P-gp, whereas cells treated with piperacillin and cefoperazone did not overexpress P-gp. MCF-7/doxy cells were compared to a positive-control subline, MCF-7/Adr, previously selected for doxorubicin resistance, and to MCF-7 cells treated with doxorubicin (MCF-7/doxo). All three sublines overexpressed P-gp and MDR1 mRNA and accumulated less intracellular doxorubicin than did control MCF-7 cells. P-gp expression was induced only by experimental drugs that were cytotoxic (doxorubicin and doxycycline). Doxycycline, a drug that has been used for treatment of bacterial infections in cancer patients, can induce functional P-gp expression in cancer cells, resulting in multidrug resistance.In 1970, Biedler and Riehm (3) described an in vitro model of chemotherapeutic multidrug resistance (MDR) in which cultured cells that were selected for growth in actinomycin D developed resistance to a variety of structurally and functionally diverse cytotoxic compounds. Further studies showed that the emergence of MDR was associated with increased levels of a transmembrane glycoprotein (24), P glycoprotein (P-gp). P-gp, the product of the MDR1 gene, is a 170-kDa protein that functions as an energy-dependent drug efflux pump whose substrates include naturally occurring, lipophilic agents with a complex ring structure such as Vinca alkaloids, anthracyclines, epipodophyllotoxins, and certain rhodamine dyes (18,26,37). Exposure of tumor cells to any of these substrates can generate overexpression of P-gp, resulting in the MDR phenotype.Drug exposure is thought to cause overexpression of P-gp by both selection of resistant cells and induction of P-gp expression at the level of the MDR1 promoter (14, 34). The MDR1 promoter contains a heat-shock consensus element (46) and a putative xenobiotic response element that responds directly to treatment with cytotoxic agents (25,45), supporting th...

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Relevance of the chemical charge of rhodamine dyes to multiple drug resistance

Cited by 69 publications

References 7 publications

Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines

Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines

P‐glycoprotein‐mediated efflux of hydroxyrubicin, a neutral anthracycline derivative, in resistant K562 cells

Doxycycline Induces Expression of P Glycoprotein in MCF-7 Breast Carcinoma Cells

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