Regulation of initial vinblastine influx by P-glycoprotein

Shalinsky, David R.; Jekunen, Antti; Alcaraz, John E.; Christen, R; Kim, S.; Khatibi, Seyed Mahdi Hosseiniyan; Howell, S B

doi:10.1038/bjc.1993.6

Cited by 40 publications

(26 citation statements)

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“…Initial VBL influx (< 120 s) in KB-GRCI cells is energy-dependent and immediately potentiated by dipyridamole and verapamil (Shalinsky et al, 1993), indicating the presence of PGP's rapid efflux activity. Furthermore, DDF has been shown to inhibit PGP-associated chloride channel activity within 30 s of exposure (Valverde et al, 1992), substantiating that diterpene modulators can rapidly alter PGP function.…”

Section: Discussionmentioning

confidence: 97%

“…Modulation of influx and uptake An ability of PGP to efflux drug during the initial seconds of exposure has been established in KB-GRCI (Shalinsky et al, 1993) and other MDR tumour cells (Cano-Gauci et al, 1990). Initial VBL influx (< 120 s) in KB-GRCI cells is energy-dependent and immediately potentiated by dipyridamole and verapamil (Shalinsky et al, 1993), indicating the presence of PGP's rapid efflux activity.…”

Section: Discussionmentioning

confidence: 99%

“…However, there was a more pronounced effect of DDF and DF on [3H]-VBL influx in the KB-3-1 cells than was predicated from the magnitude of the effect of these agents at 1 h. The influx data were well fit by a straight line (r2> 0.94). Table I (Shalinsky et al, 1993). dKK vs MM control: P-value <0.001.…”

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confidence: 99%

“…Modulation of influx We have previously described the presence of a rapidly-acting PGP efflux transporter in KB-GRC1 cells that functions to reduce VBL uptake even during the initial seconds of exposure (Shalinsky et al, 1990b;Shalinsky et al, 1993). In a direct comparison between KB-GRC1 and KB-3-1 cells, the lowered apparent influx was associated only with the enhanced efflux in KB-GRCI, indicating that the PGP efflux activity manifested as both reduced influx and enhanced efflux.…”

mentioning

confidence: 99%

“…Uptake was determined as previously described (Shalinsky et al, 1993). Briefly, aliquots of a subsequently homogenised cellular suspension were used for determination of protein content and cell-associated radioactivity.…”

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confidence: 99%

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Selective modulation of vinblastine sensitivity by 1,9-dideoxyforskolin and related diterpenes in multidrug resistant tumour cells

Shalinsky

Heath²,

Jekunen³

et al. 1993

Br J Cancer

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Summary The ability of 1,9-dideoxyforskolin (DDF), 1-deoxyforskolin (DF) and forskolin to modulate cellular sensitivity to vinblastine (VBL) was examined in drug-sensitive parental KB-3-1 cells and a multidrugresistant subline, KB-GRC1, derived by transfection of mdrl. Fifty gM DF and forskolin enhanced the 1 h uptake of VBL by 8.0 ± 0.7 (s.d.) and 4.7 ± 2.5-fold, respectively, with 501lM DDF producing a 13.6 ± 1.9-fold increase. The greater effect of DDF relative to forskolin indicated that the effect was independent of activation of cAMP, and this was supported by a lack of effect of dibutyryl cAMP on the uptake. The effect of these agents on uptake were < 1.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Selective modulation of vinblastine sensitivity by 1,9-dideoxyforskolin and related diterpenes in multidrug resistant tumour cells

Shalinsky

Heath²,

Jekunen³

et al. 1993

Br J Cancer

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Effect of combination of suboptimal concentrations of P-glycoprotein blockers on the proliferation ofMDR1 gene expressing cells

et al. 1996

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Pharmacologically active in vivo doses of P-glycoprotein (Pgp) blockers, specifically verapamil, Cremophor EL and PSC833 cause toxicity in addition to that from the concomitantly used cancer chemotherapeutic drugs. It was shown before that these blockers cause different types of toxicities in vivo. We found that these 3 chemically distinct Pgp blockers exert different biophysical effects on the membranes of LIZ10 MDR cells. They also affect the general metabolism of these cells differently, but all block affinity labeling of Pgp. We could also show that the combination of suboptimal doses of these blockers can restore the uptake of the Pgp substrate rhodamine I23 into L I 2 I OMDR, 3T3MDR and KB-VI cells and can reduce the survival rate of these cells when treated in combination with daunorubicin. Our results suggest that the combination of suboptimal doses of these Pgp blockers may be advantageous in clinical practice.

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Flow cytometric assessment of the cellular pharmacokinetics of fluorescent drugs

Dordal

Jackson-Stone

et al. 1995

Cytometry

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Development of multidrug resistance (MDR) in cancer cells decreases net doxorubicin uptake as a result of either increased efflux, or decreased intracellular sequestration, or decreased membrane permeability. Kinetic parameters of drug uptake can distinguish among these forms of altered transport. Cellular uptake of fluorescent drugs was monitored by a flow cytometric assay using a rapid-injection system and analyzed with a three-compartment model in which rapid diffusion from extracellular fluid into the cell was followed by uptake into a nonexchangeable pool. In agreement with our recent studies of '*C-doxorubicin distribution (Dordal et al.: J Pharmacol Exp Ther 271:12861290, 1994), sequestration of doxorubicin was decreased 2.7-fold in P-glycoprotein-expressing SU-4R lymphoma cells compared to drug-sensitive SU-4 cells Malignant cells may become resistant to anticancer drugs by the overexpression of proteins that alter net cellular drug accumulation. Clinically significant resistance to anthracyclines, vinca alkaloids, and other natural products has been reported in association with increased expression of P-glycoprotein, the most widely studied of these proteins (9,ll). More recently, intracellular proteins have been described that are found in resistant cells that do not express P-glycoprotein but do exhibit a similar phenotype (4,16). P-glycoprotein is believed to act as a drug efflux pump, because cell lines expressing the protein lose intracellular drug much more quickly than their nonresistant progenitors when transferred to drug free medium.However, our recent studies of multidrug-resistant HL-60 and SU-4 subclones suggested that, in these cell lines, the most significant alteration in doxorubicin transport was decreased sequestration in a nonexchangeable compartment (7). The result was that proportionally more intracellular drug existed in exchangeable compartments, where it could freely diffuse from the cell. Drugresistant cells showed no evidence of active efflux (14.0 2 4.8 vs. 5.0 f 0.9 nl s-') without a change in membrane permeability or evidence of active efflux. In contrast, sequestration of the highly fluorescent dye rhodamine 123 was decreased 20-fold (17.1 f 8.3 vs. 0.9 f 0.8 nl s-'). Resistant

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Regulation of initial vinblastine influx by P-glycoprotein

Cited by 40 publications

References 30 publications

Selective modulation of vinblastine sensitivity by 1,9-dideoxyforskolin and related diterpenes in multidrug resistant tumour cells

Selective modulation of vinblastine sensitivity by 1,9-dideoxyforskolin and related diterpenes in multidrug resistant tumour cells

Effect of combination of suboptimal concentrations of P-glycoprotein blockers on the proliferation ofMDR1 gene expressing cells

Flow cytometric assessment of the cellular pharmacokinetics of fluorescent drugs

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