Differential modulation of P-glycoprotein transport by protein kinase inhibition

Bates, Susan E.; Lee, Jong Seok; Dickstein, Bruce; Spolyar, Mary; Fojo, Antonio Tito

doi:10.1021/bi00086a022

Cited by 89 publications

(55 citation statements)

References 33 publications

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“…PKC activators also increased drug accumulation and decreased drug sensitivity in MCF-7/Adr (Fine et al, 1988) and KM12L4a cells (Dong et al, 1991), and induced MDRJ gene expression in normal human lymphocytes (Chaudhary and Roninson, 1992). Conversely, a variety of PKC inhibitors, such as staurosporine (Sato et al, 1990), the staurosporine analogues CGP 41251 (Utz et al, 1994; Budworth et al, 1996) and GF 109203X , calphostin C (Bates et al, 1993) and safingol (Sachs et al, 1995), reversed P-gp-mediated mdr. However, reversal of drug resistance caused by staurosporine analogues is probably associated with direct interaction with P-gp rather than with PKC inhibition (Smith and Zilfou, 1995;Gekeler et al, 1996;Goodfellow et al, 1996;Budworth et al, 1996).…”

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confidence: 99%

Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells

Budworth

Gant²,

Gescher³

1997

Br J Cancer

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Summary The aim of this study was to investigate the link between protein kinase C (PKC) and multidrug resistance (mdr) phenotype. The expression of both was studied in doxorubicin-resistant MCF-7/Adr cells as they reverted to the wild-type phenotype when cultured in the absence of drug. The following parameters were measured in cells 4, 10, 15, 20 and 24 weeks after removal of doxorubicin; (1) sensitivity of the cells towards doxorubicin; (2) levels of P-glycoprotein (P-gp) and MDR1 mRNA; (3) levels and cellular localization of PKC isoenzyme proteins cx, 0 and e; and (4) gene copy number of PKC-a and MDR1 genes. Cells lost their resistance gradually with time, so that by week 24 they had almost completely regained the drug sensitivity seen in wild-type MCF-7 cells. P-gp levels measured by Western blot mirrored the change in doxorubicin sensitivity. By week 20, P-gp had decreased to 18% of P-gp protein levels at the outset, and P-gp was not detectable at week 24. Similarly, MDR1 mRNA levels had disappeared by week 24. MCF-7/Adr cells expressed more PKCs-a and -0 than wild-type cells and possessed a different cellular localization of PKC-c. The expression and distribution pattern of these PKCs did not change for up to 20 weeks, but reverted back to that seen in wild-type cells by week 24. MDR1 gene amplification remained unchanged until week 20, but then was lost precipitously between weeks 20 and 24. The PKC-a gene was not amplified in MCF-7/Adr cells. The results suggest that MCF-7/Adr cells lose MDR1 gene expression and PKC activity in a co-ordinate fashion, consistent with the existence of a mechanistic link between MDR1 and certain PKC isoenzymes.

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confidence: 99%

Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells

Budworth

Gant²,

Gescher³

1997

Br J Cancer

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“…Se ha demostrado que la exposición de células con fenotipo MDR a activadores de PKC aumenta la fosforilación de la Pgp, disminuye la acumulación del medicamento e incrementa la resistencia a los fármacos (101,102); al contrario, la presencia de inhibidores de PKC disminuye la fosforilación e incrementa la acumulación del medicamento (103).…”

Section: Posibles Estrategias Para Revertir El Fenotipo Mdrunclassified

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

et al. 2005

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Actualmente, los parásitos protozoarios son uno de los principales agentes causantes de morbilidad y mortalidad en el mundo, un problema complicado, además, por la aparición de resistencia a medicamentos en estos organismos. La resistencia a medicamentos observada en parásitos protozoarios se debe a diferentes mecanismos como la disminución de la entrada del medicamento a la célula por cambios en el transportador requerido, la pérdida de la activación del medicamento por parte del hospedero, las alteraciones en el blanco del medicamento y la expresión exagerada del transportador múltiple de medicamentos o glicoproteína P (Pgp). En esta revisión, nos centramos en: 1) el papel de las glicoproteínas P (Pgp) de la familia de proteínas ABC (ATP binding cassette) como los transportadores de múltiples medicamentos en la mediación de resistencia en protozoarios, especialmente en Leishmania, y en el desarrollo de resistencia cruzada para medicamentos estructural y funcionalmente no relacionados, y 2) en algunos conceptos relacionados con los mecanismos moduladores que podrían revertir la resistencia a medicamentos por fármacos y productos naturales. Numerosos moduladores o quimiosensibilizadores son conocidos por alterar la capacidad de las glicoproteínas P para mantener concentraciones intracelulares subtóxicas del medicamento; algunos ejemplos incluyen los bloqueadores de los canales de calcio como el verapamilo; sin embargo, se requieren altas concentraciones para una inhibición eficiente y duradera, las cuales producen efectos adversos indeseables. Por tanto, se necesitan más investigaciones relacionadas con los moduladores naturales para Pgp, los cuales podrían presentar menor toxicidad para el hospedero.Palabras clave: Leishmania, protozoos, multirresistencia, glicoproteína P, productos naturales. Leishmania: role of P glycoprotein in drug resistance and reversion strategiesProtozoan parasites are important causative agents of morbidity and mortality throughout the world -a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as verapamil act in this mode; however, high concentrations are required for an efficient and effective inhibition and, in addition, produce undesirable side effects. The di...

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“…A popular and widely used compound is the protein kinase C activator TPA, first reported by Hamada et al (1987) to stimulate P-glycoprotein phosphorylation, and first reported by Fine et al (1988) to influence MDR drug accumulation. Short-term TPA treatment stimulates P-glycoprotein phosphorylation and reduces drug accumulation in a wide variety of MDR cell lines (Aftab et al, 1994;Bates et al, 1992;Bates et al, 1993;Chambers et al, 1990;Chambers et al, 1992;Yu et al, 1991). The effect of TPA on drug accumulation is dose-dependent, with a half-maximal effect at around 20 nM TPA, and is observed in MDR cells and not in the respective drug-sensitive cell line (Aftab et al, 1994;Chambers et al, 1992).…”

Section: Phosphorylation Of P-glycoproteinmentioning

confidence: 99%

“…Increased drug accumulation occurs in MDR cell lines treated with staurosporine or calphostin C, both effective inhibitors of P-glycoprotein phosphorylation (Aftab et al, 1994;Bates et al, 1993;Chambers et al, 1992;Ma et al, 1991). Sodium butyrate has also been shown to inhibit P-glycoprotein phosphorylation and cause an increase in accumulation of several cytotoxic drugs that are substrate for P-glycoprotein (Bates et al, 1992).…”

Section: Phosphorylation Of P-glycoproteinmentioning

confidence: 99%

Molecular analysis of the multidrug transporter, P-glycoprotein

Germann

Chambers

1998

Multiple Drug Resistance in Cancer 2

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Inherent or acquired resistance of tumor cells to cytotoxic drugs represents a major limitation to the successful chemotherapeutic treatment of cancer. During the past three decades dramatic progress has been made in the understanding of the molecular basis of this phenomenon. Analyses of drug-selected tumor cells which exhibit simultaneous resistance to structurally unrelated anti-cancer drugs have led to the discovery of the human MDR1 gene product, P-glycoprotein, as one of the mechanisms responsible for multidrug resistance. Overexpression of this 170 kDa N-glycosylated plasma membrane protein in mammalian cells has been associated with ATPdependent reduced drug accumulation, suggesting that P-glycoprotein may act as an energy-dependent drug efflux pump. P-glycoprotein consists of two highly homologous halves each of which contains a transmembrane domain and an ATP binding fold. This overall architecture is characteristic for members of the ATP-binding cassette or ABC superfamily of transporters. Cell biological, molecular genetic and biochemical approaches have been used for structure-function studies of P-glycoprotein and analysis of its mechanism of action. This review summarizes the current status of knowledge on the domain organization, topology and higher order structure of P-glycoprotein, the location of drug-and ATP binding sites within P-glycoprotein, its ATPase and drug transport activities, its possible functions as an ion channel, ATP channel and lipid transporter, its potential role in cholesterol biosynthesis, and the effects of phosphorylation on P-glycoprotein activity.

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Differential modulation of P-glycoprotein transport by protein kinase inhibition

Cited by 89 publications

References 33 publications

Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells

Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

Molecular analysis of the multidrug transporter, P-glycoprotein

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