Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human multidrug-resistant cells, K562/ADM, KB-C-4, AdrRMCF-7 and CEM/VLB100 showed 21-, 7.5-, 105- and 3.4-fold cross-resistance to mitomycin C (MMC). The resistance to MMC in K562/ADM, KB-C-4, AdrRMCF-7, CEM/VLB100 cells was reversed by 6.6 microM verapamil. Accumulation of [3H]MMC in K562/ADM, AdrRMCF-7 and CEM/VLB100 cells also decreased by 37, 26 and 33%, as compared with their drug-sensitive counterparts. In KB-C-4 cells, accumulation of [3H]MMC decreased by 60%, and efflux rate of [3H]MMC was slightly increased as compared to their parental KB-3-1 cells. Verapamil at 6.6 microM increased accumulation of [3H]MMC in these multidrug-resistant sublines. K562/ADM10, K562/ADM50, K562/ADM100 and K562/ADM250 cells, which showed 17- to 230-fold resistance to Adriamycin, also showed 0.8- to 7.3-fold cross-resistance to MMC. In these cell lines, the extent of resistance to Adriamycin (ADM) that was consistent with expression levels of P-glycoprotein shown by immunoblotting was directly proportional to the extent of their resistance to MMC. Regression analysis indicated that relative resistance to Adriamycin was correlated with relative resistance to MMC (r = 0.98). These results indicate that MMC can be transported by P-glycoprotein overexpressed in multidrug-resistant cells.
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PMID:Cross-resistance of human multidrug-resistant cells to mitomycin C. 190 15

Verapamil enhances anticancer drug cytotoxicity in multidrug resistant (MDR) cells, apparently by competing with these agents for binding to P-glycoprotein (Pgp). In this study, we provide direct evidence for this competition. We studied the binding of an optically pure photoaffinity analogue of verapamil, (S)-5-[(3-azidophenylethyl)-[N-methyl-3H]- methylamino]-2-(3,4,5-trimethoxyphenyl)-2-isopropylvaleronitrile (LU-49888), to Pgp from MDR cell lines. LU-49888 specifically labeled a single Mr 170,0000 protein that was identified as Pgp on Western blots and also by specific immunoprecipitation with monoclonal antibody C-219. A 200-fold molar excess of vinblastine or vincristine specifically inhibited this binding by greater than 98%. LU-49888 labeling of Pgp was also inhibited by actinomycin D (45%), podophyllotoxin (47%), and amsacrine (82%), marginally by doxorubicin (25%), colchicine (22%), daunorubicin (18%), and etoposide (14%), but not by teniposide. Modulators of Pgp-MDR also compete with LU-49888 for binding to Pgp: verapamil (82%), diltiazem (73%), quinidine (91%), reserpine (91%), rescinnamine (88%), and trimethoxybenzoylyohimbine (89%). Chloroquine was moderately inhibitory (25%), whereas chlorpromazine and yohimbine, which are not modulators in our MDR cell lines, did not inhibit the binding of LU-49888 to Pgp. LU-49888 labeling of Pgp was also completely inhibited by (R)-, (S)-, and racemic desmethoxyverapamil, all with the same efficiency. Our results demonstrate that the verapamil analogue LU-49888 specifically binds to Pgp and suggest that verapamil and some MDR modulators exert their effects by interacting with Pgp.
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PMID:Binding of an optically pure photoaffinity analogue of verapamil, LU-49888, to P-glycoprotein from multidrug-resistant human leukemic cell lines. 196 51

Vincristine (Vcr) dose dependently inhibited growth of the kidney adenocarcinoma cell line ACHN during 4 days of culture. Verapamil (Ver) at 10 microM and cyclosporin A (CsA) at 1 microgram/ml had no effect on cell growth but significantly potentiated the action of Vcr, despite the absence of the multidrug resistance associated membrane P-glycoprotein (P-gp). Neither Ver nor CsA had any acute or long term effects on cytoplasmic free Ca2+ concentration (Ca2+i), except for a small Ver induced increase after 36 h of incubation. The results indicate that Ver and CsA may have a sensitizing effect on chemotherapeutic drug sensitivity also in absence of P-gp. However, these effects are probably not mediated by changes in Ca2+i.
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PMID:Verapamil and cyclosporin A sensitize human kidney tumor cells to vincristine in absence of membrane P-glycoprotein and without apparent changes in the cytoplasmic free Ca2+ concentration. 197 32

The interaction of etoposide (VP-16), Vinca alkaloids, and verapamil with the P-glycoprotein (P-gp) was studied in human breast (MCF-7) and Chinese hamster lung (DC3F) cell lines and the corresponding multidrug-resistant MCF-7/ADR and DC3F/ADX tumor cell lines, selected for resistance to Adriamycin and actinomycin D, respectively, and overexpressing P-gp. Verapamil (10 microM) markedly reversed resistance to vincristine (11-fold in DC3F/ADX and 125-fold in MCF-7/ADR; 1-hr exposure), but it had a very modest effect on resistance to VP-16 (3- to 4-fold; 1-hr exposure). Resistant cells accumulated 2- to 4-fold less VP-16 and vincristine than the parental cell lines. Verapamil (10 microM) significantly increased accumulation and retention of vincristine, but not of VP-16, in resistant cell lines. Photoaffinity labeling of resistant cell lines with radioactive analogs of verapamil [N(p-azido-3-125I-salicyl)-N'-beta-aminoethylverapamil (NASVP)] and vinblastine[N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine (NASV)] showed distinctly labeled P-gp bands in both resistant cell lines, compared with wild-type cells. Excess nonradioactive vinblastine or verapamil effectively competed with the P-gp photolabeling by either NASVP or NASV, with IC50 levels of 0.6 and 10 microM, respectively. In contrast, nonradioactive VP-16 was 100- to 500-fold less potent than vinblastine in competing with P-gp photolabeling, suggesting that VP-16 has significantly lower affinity for P-gp than Vinca alkaloids have. Taken together, our data indicate that P-gp glycoprotein by itself may not be important in the transport/efflux of VP-16 and, thus, in the mechanism of resistance to VP-16 in these cells.
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PMID:P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies. 197 71

We have developed three adriamycin (ADR)-resistant K562 sublines with different degrees of resistance. These sublines show a decreased accumulation and an increased efflux of ADR in proportion to the degree of resistance. Two membrane proteins (mol. wt 170,000 and 230,000) reactive with monoclonal antibody against P-glycoprotein were highly expressed in both the K562/ADR200 and the K562/ADR500 subline. Less resistant K562/ADR80 cells contained only small amounts of mol. wt 230,000 protein. Thus, the level of P-glycoprotein expression was not proportionate to the degree of ADR efflux. Verapamil treatment could not completely reverse ADR resistance. No significant change of glutathione-s-transferase activity nor in the level of DNA topoisomerase II was detected in resistant sublines. In our sublines it seems that P-glycoprotein is one of the mechanisms for resistance, but additional mechanisms may be involved.
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PMID:Mechanisms involved in the development of adriamycin resistance in human leukemic cells. 197 51

Agents capable of reversing multidrug resistance (mdr) in falciparum malaria were investigated for potentiation of chloroquine accumulation and toxicity in a cell culture system. Verapamil, its analog RO11-2933, and desipramine caused a dose-dependent increase in the accumulation of chloroquine (CQ) within human and mouse hepatocytes but not human lung cells. Only those cells in which drug accumulation was enhanced by reversing agents reacted positively for P-glycoprotein (PgP)--the putative mediator of the enhanced drug efflux characteristic of mdr. Clinically achievable concentrations of verapamil (0.4 microM) and desipramine (1 microM) increased CQ accumulation within primary mouse hepatocytes by more than 50%. A well-differentiated normal human cell line (Hep-G2) was killed in media containing a combination of supraphysiological concentrations of CQ and verapamil but survived the same concentrations of either drug alone. Reversing agents may block PgP-mediated drug export from normal tissues as well as from MDR cells. Iatrogenic toxicity resulting from this accumulation of potentially toxic drugs such as CQ within normal cells could complicate the reversal of mdr in vivo.
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PMID:Reversal of drug-resistant falciparum malaria by calcium antagonists: potential for host cell toxicity. 197 36

Verapamil has been proposed to modulate the multidrug resistance phenotype by competitive inhibition of an energy dependent efflux of cytotoxic drug. However, the accumulation of both 14C-verapamil and 3H-verapamil was similar in wild type EHR2 and multidrug resistant EHR2/DNR+ Ehrlich ascites cells, and was much less in both cell lines in energy deprived medium than in medium containing glucose. Azidopine accumulation was also similar in both EHR2 and EHR2/DNR+ cells but, in contrast to verapamil, did not differ significantly with changes in cellular energy levels. Azidopine photolabelled a 170 kDa protein in EHR2/DHR+ plasma membrane vesicles which was immunoprecipitated by monoclonal antibody towards P-glycoprotein. Azidopine increased daunorubicin accumulation and modulated vincristine resistance in EHR2/DNR+ cells in a similar fashion to verapamil. Azidopine photolabelling was inhibited by vincristine and verapamil, but not by daunorubicin. Vincristine, but not daunorubicin, was able to increase both azidopine and verapamil accumulation in EHR2/DNR+ cells only. Finally, though both verapamil and azidopine are a substrate for P-glycoprotein in EHR2/DNR+ cells, they do not themselves appear to be transported by the multidrug resistance efflux mechanism to any significant extent in these cells.
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PMID:Transport of the multidrug resistance modulators verapamil and azidopine in wild type and daunorubicin resistant Ehrlich ascites tumour cells. 197 2

A newly established gastric carcinoma cell line (EPG85-257P) exhibited a high sensitivity to mitoxantrone (DHAD) as determined by a monolayer proliferation assay. The concentration to inhibit cell growth to 50% of controls (IC50) was 0.0022 micrograms/ml culture medium. The cells were continuously incubated for more than 4 months in the presence of stepwise increased concentrations of DHAD, and the IC50 was increased to 0.41 micrograms/ml, i.e., 186.4-fold. This resistant variant was named EPG85-257RNOV. The EPG85-257RNOV cells became cross-resistant to Adriamycin with enhanced IC50 by 10.5-fold and to daunomycin with enhanced IC50 by 3.9-fold. No distinct resistance was observed to vinblastine, vincristine, and colchicine. Verapamil (10(-6), 4 X 10(-6) and 10(-5) M) and cyclosporin A (10(-6), 3 X 10(-6) and 10(-5) M) did not reverse DHAD resistance. As shown by immunocytochemistry (monoclonal antibodies: C219 and JSB-1) and Northern blot analysis, DHAD resistance was not associated with the appearance of the multidrug resistance (MDR)-associated (Mr 170,000) P-glycoprotein or the overexpression of P-glycoprotein mRNA. The data indicate a chemoresistance pattern unlike typical MDR (often called "atypical" MDR). The phenotypes of parent and resistant EPG85-257 cells were compared using interference contrast microscopy, electron microscopy, and immunocytochemistry. After DHAD application the following structural characteristics were found to be associated with emergence of resistance: (a) intensive formation of surface vesicles in the resistant variant. Such vesicles were almost absent in sensitive cells; (b) the vesicles contained the selecting DHAD which was visualized by its blue color; and (c) in electron microscopy the vesicles were formed by an inner and an outer double membrane, presumably derived from the plasmalemma. These observations suggest a complex cellular mechanism responsible for DHAD resistance which includes formation of membrane vesicles, vesicular drug binding, and drug compartmentalization.
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PMID:Membrane vesicle formation due to acquired mitoxantrone resistance in human gastric carcinoma cell line EPG85-257. 197 14

The TT-cell line, derived from a patient with metastatic medullary thyroid carcinoma (MTC), was found to exhibit intrinsic resistance to vincristine (VCR) despite the absence of immunohistochemically detectable 170 kDa P-glycoprotein (PGP 170) associated with multidrug resistance (MDR). Verapamil and cyclosporin A, two well known resistance modifiers of MDR, were found to significantly potentiate the action of VCR (60-fold) and to a lesser degree also of VP-16 and daunorubicin (dnr). The present results suggests that resistance of MTC to chemotherapy may be at least partly circumvented by the addition resistance modifiers to chemotherapeutic regimens.
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PMID:Verapamil and cyclosporin A potentiate the effects of chemotherapeutic drugs in the human medullary thyroid carcinoma TT cell line not expressing the 170 kDa P-glycoprotein. 197 12

First-step Adriamycin (doxorubicin)-resistant mutants of the murine erythroleukemia cell line PC4 were cloned from Adriamycin-containing (10 ng/ml) methylcellulose at a frequency of 3 x 10(-4). They demonstrated 1.6- to 2.4-fold stable resistance to Adriamycin. Most were cross-resistant to etoposide, but not to vincristine, and were without enhanced expression of mdr genes, which code for P-glycoproteins. Two different murine erythroleukemia cell lines, PC4 and C7D, were passaged in suspension culture into stepwise increasing amounts of Adriamycin. No high-level resistant mutants were isolated de novo; cells initially displayed low-level resistance to Adriamycin and etoposide. Two stepwise doublings of the drug concentration were needed before PC4 cells acquired vincristine resistance, but there was no detectable overexpression of mdr or a change in anthracycline uptake. In a subsequent doubling of Adriamycin concentration, the cells showed a further increase in resistance to all three drugs and now a decreased anthracycline accumulation. However, there was still no detectable increase in mdr expression as judged by Northern analysis of poly(A)+ enriched RNA and Western blot analysis of membrane proteins. Only after a fourth doubling of Adriamycin concentration did the cells demonstrate enhanced expression of mdr and P-glycoprotein. Equivalent mutants of C7D were selected, but generally at lower Adriamycin concentrations. Verapamil partially lowered resistance, but failed to restore parental susceptibility in any mutant; it caused an increased uptake in those mutants showing decreased anthracycline accumulation, including those that did not overexpress mdr. This study demonstrated different resistance phenotypes among mutants appearing spontaneously under stepwise drug selection; mutants with vincristine resistance and decreased anthracycline uptake preceded those associated with over-expression of P-glycoprotein.
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PMID:Sequential emergence of distinct resistance phenotypes in murine erythroleukemia cells under adriamycin selection: decreased anthracycline uptake precedes increased P-glycoprotein expression. 197 51


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