Circumvention of Multidrug Resistance Mediated by P-170 Glycoprotein Using Calcium Antagonists in Primary Human Renal Cell Carcinoma

Mickisch, G.; Kössig, Jutta; Tschada, R.; Keilhauer, Gerhard; Schlick, E.; Alken, P.

doi:10.1159/000282204

Cited by 12 publications

(8 citation statements)

References 5 publications

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“…Several authors have reported the inhibition of these proteins with different classes of drugs in multiresistant cancer cells (32). Promising experimental results found a partial confirmation in clinical trials in the treatment of different types of solid tumors (25,44) and hematologic malignancies (17,19,20,41,42). A similar experimental principle had already been investigated to reverse the chloroquine resistance in Plasmodium falciparum (3) or the resistance to quinolone antibiotics in Staphylococcus aureus (15).…”

mentioning

confidence: 97%

Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans

Marchetti¹,

Moreillon²,

Glauser³

et al. 2000

Antimicrob Agents Chemother

234

192

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Several types of drugs currently used in clinical practice were screened in vitro for their potentiation of the antifungal effect of the fungistatic agent fluconazole (FLC) on Candida albicans. These drugs included inhibitors of multidrug efflux transporters, antimicrobial agents, antifungal agents, and membrane-active compounds with no antimicrobial activity, such as antiarrhythmic agents, proton pump inhibitors, and platelet aggregation inhibitors. Among the drugs tested in an agar disk diffusion assay, cyclosporine (Cy), which had no intrinsic antifungal activity, showed a potent antifungal effect in combination with FLC. In a checkerboard microtiter plate format, however, it was observed that the MIC of FLC, as classically defined by the NCCLS recommendations, was unchanged when FLC and Cy were combined. Nevertheless, if a different reading endpoint corresponding to the minimal fungicidal concentration needed to decrease viable counts by at least 3 logs in comparison to the growth control was chosen, the combination was synergistic (fractional inhibitory concentration index of <1). This endpoint fitted to the definition of MIC-0 (optically clear wells) and reflected the absence of the trailing effect, which is the result of a residual growth at FLC concentrations greater than the MIC. The MIC-0 values of FLC and Cy tested alone in C. albicans were >32 and >10 g/ml, respectively, and decreased to 0.5 and 0.625 g/ml when the two drugs were combined. The combination of 0.625 g of Cy per ml with supra-MICs of FLC resulted in a potent antifungal effect in time-kill curve experiments. This effect was fungicidal or fungistatic, depending on the C. albicans strain used. Since the Cy concentration effective in vitro is achievable in vivo, the combination of this agent with FLC represents an attractive perspective for the development of new management strategies for candidiasis.Candida infections represent an increasing challenge for clinicians. The epidemiology of the last decade shows that these infections are continuously increasing (1), owing to more aggressive management of medical and surgical cases. Fluconazole (FLC) has been shown to be as effective as amphotericin B in the treatment of candidemia in non-neutropenic patients (35). Since amphotericin B is toxic in its conventional form and very expensive in its new lipidic forms, azole antifungal agents are currently used as first-line drugs (6, 11). Nevertheless, the emergence of Candida albicans strains with decreased susceptibility to FLC and the epidemiologic shift to other Candida species complicate the management of these infections (5,28,45). Among azole antifungal agents, FLC offers several advantages, such as an excellent oral bioavailability, a stable parenteral formulation, and minimal drug interactions. However, FLC, like the other azole derivatives, is only fungistatic. Its efficacy relies on the function of the cellular host defenses (10) and is limited in cases of profound neutropenia (4, 6) or by severe depletion of CD4 cells (36). Thus, the pot...

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mentioning

confidence: 97%

Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans

Marchetti¹,

Moreillon²,

Glauser³

et al. 2000

Antimicrob Agents Chemother

234

192

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“…For example, verapamil and propafenone both inhibit digoxin-transport in P-glycoprotein-expressing cell lines (Cavet et al 1996;Woodland et al 1997). In vitro studies in renal cell carcinoma revealed that calcium antagonists such as verapamil showed the strongest reversal of chemoresistance, but derivatives of the benzothiazepine type (diltiazem) acted similarly and reached about 70% of the verapamil activity (Mickisch et al 1991). Animal models have provided evidence of the P-glycoprotein-inhibiting properties of amiodarone (Arboix et al 1997).…”

Section: Discussionmentioning

confidence: 99%

“…For digitoxin elimination of the parent compound or metabolites occurs via bile and urine. Elevated plasma levels of digitoxin and digoxin derivatives have been described under concomitant use with other drugs (De Cesaris et al 1983a, 1983bLaer et al 1998) which are known to inhibit P-glycoprotein function (Arboix et al 1997;Cavet et al 1996;Mickisch et al 1991;van der Graaf et al 1991). The mechanism of these interactions has not yet been identified, but an involvement of P-glycoprotein might be suspected.…”

Section: Introductionmentioning

confidence: 99%

P-glycoprotein-mediated transport of digitoxin, α-methyldigoxin and β-acetyldigoxin

Pauli‐Magnus

Mürdter

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

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Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.

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“…Subsequently, they also evaluated the efficacy of various modulators on the intrinsic MDR of RCC specimens, e.g. a calcium‐channel blocker (verapamil) and glutathione inhibitor (buthionine sulphoximine), finding a dramatic effect [ 13, 14].…”

Section: Discussionmentioning

confidence: 99%

The expression of mdr‐1‐related gp‐170 and its correlation with anthracycline resistance in renal cell carcinoma cell lines and multidrug‐resistant sublines

Chang

1998

British Journal of Urology

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Objectives To clarify the role of the membranous glycoprotein gp‐170 in renal cell carcinoma (RCC) cell lines and their multidrug resistant (MDR) sublines, and to correlate gp‐170 with the natural and acquired drug resistance of these cell lines to anthracyclines. Materials and methods The expression of gp‐170 in five cultured RCC cell lines and serial RCC8701 MDR sublines was analysed by immunofluorescent flow cytometry. The chemosensitivity of these tumour cells to the anthracycline anticancer drugs adriamycin and epirubicin was measured using the microplate tetrazolium (MTT) cytotoxicity assay, and the results correlated with gp‐170 expression. Results All six natural RCC cell lines showed a variably increased expression of gp‐170, with the A704 and Caki‐1 cell lines the highest. In contrast, gp‐170 expression increased and then was suppressed in acquired MDR sublines of RCC8701 cultured in increasing concentrations of adriamycin. The A704 and Caki‐1 cells were much more resistant to adriamycin and epirubicin than the A498, ACHN and RCC8701 cell lines, in parallel with the expression of gp‐170. The resistant cell line cultured long‐term in 800 ng/mL adriamycin, RCC8701/ADR800, was 122 times more resistant to adriamycin and 238 times more resistant to epirubicin than the parent cell line; the pattern differed from that in native RCC cell lines and was unrelated to the expression of gp‐170. Conclusion Membranous gp‐170 plays an important role in MDR of native RCC cell lines, while acquired MDR cells have different mechanisms of obtaining drug resistance in addition to gp‐170. This phenomenon may be applicable to the clinical treatment of patients newly diagnosed with RCC or those with disease refractory to chemotherapy.

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Circumvention of Multidrug Resistance Mediated by P-170 Glycoprotein Using Calcium Antagonists in Primary Human Renal Cell Carcinoma

Cited by 12 publications

References 5 publications

Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans

Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans

P-glycoprotein-mediated transport of digitoxin, α-methyldigoxin and β-acetyldigoxin

The expression of mdr‐1‐related gp‐170 and its correlation with anthracycline resistance in renal cell carcinoma cell lines and multidrug‐resistant sublines

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