Reversal of Vinca alkaloid resistance but not multiple drug resistance in human leukemic cells by verapamil

Beck, W T; Cirtain, Margaret C.; Look, A.L.; Ashmun, Richard A.

doi:10.1016/0378-8741(86)90008-5

Cited by 20 publications

(28 citation statements)

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“…These results are consistent with the demonstration that verapamil was not effective in altering colchicine accumulation by MDR cells (32). Similarly, the effect of verapamil on reversing Vinca alkaloid resistance was shown to be much greater than its effect on other natural product drugs against which cells express cross-resistance (33).…”

Section: Discussionsupporting

confidence: 80%

Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil.

Safa¹

1988

Proc. Natl. Acad. Sci. U.S.A.

184

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Verapamil, a phenylalkylamine calcium channel blocker, has been shown to reverse multidrug resistance in tumor cells, possibly by increasing drug retention through interaction with an outward drug transporter of the resistant cells. In this study two photoactive radioactive analogs of verapamil, N-(p-azido[3,5-31H]benzoyl)aminomethyl verapamil and N-(p-azido[3-'25I]salicyl)aminomethyl verapamil, were synthesized and used to identify the possible biochemical target(s) for verapamil in multidrug-resistant DC-3F/VCRd-5L Chinese hamster lung cells selected for resistance to vincristine. The results show that a specifically labeled 150-to 180-kDa membrane protein in resistant cells was immunoprecipitated with a monoclonal antibody specific for Pglycoprotein. Phenylalkylamine binding specificity was established by competitive blocking ofspecific photolabeling with the nonradioactive photoactive analogs as well as with verapamil.Photoaffinity labeling was also inhibited by 50 jzM concentrations of the calcium channel blockers nimodipine, nifedipine, nicardipine, azidopine, bepridil, and diltiazem and partially by prenylamine. Bay K8644, a calcium channel agonist, also inhibited P-glycoprotein photolabeling. Moreover, P-glycoprotein labeling was inhibited in a dose-dependent manner by vinblastine with half-maximal inhibition at 0.2 jiM compared to that by verapamil at 8 jiM. Photolabeling was also partially inhibited by two of the drugs to which these cells are crossresistant, doxorubicin and actinomycin D, at 100 jM, but not by colchicine. These data provide direct evidence that Pglycoprotein has broad drug recognition capacity and that it serves as a molecular target for calcium channel blocker action in reversing multidrug resistance.Multidrug resistance (MDR) refers to patterns of crossresistance that develop in tumor cells selected by using a single natural-product drug. Exposure to agents such as vinblastine, vincristine, doxorubicin, or colchicine confers resistance to a wide range of compounds with no apparent structural or functional similarities (1, 2) to the selective agent. MDR is frequently characterized by diminished drug accumulation in resistant cells compared to drug-sensitive cells (3,4). This reduced accumulation often correlates with the concomitant over-expression of a 150-to 180-kDa integral membrane glycoprotein, P-glycoprotein (P-gp) or gp150-180, which is produced in MDR cells in proportion to their level of drug resistance (5-7). Experiments with vinblastine photoactive analogs revealed the specific interaction of vinblastine with P-gp in plasma membranes from MDR cells and suggested that this protein may mediate cellular drug accumulation by binding to drugs and regulating their membrane transport (8,9). Based on sequence data, it has been shown that significant homology exists between P-gp and bacterial transport proteins, that P-gp has two nucleotide binding domains (10-12) that bind ATP (13), that the gene coding for this protein generates the MDR phenotype when transfected into dru...

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Section: Discussionsupporting

confidence: 80%

Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil.

Safa¹

1988

Proc. Natl. Acad. Sci. U.S.A.

184

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“…When present in combination with vinblastine, rescinnamine, trimethoxybenzoylyohimbine, reserpine, benzoylyohimbine, and 18-epireserpine produced a concentration-dependent increase in vinblastine cytotoxicity (decrease in IC50) in our multidrug-resistant cells (Fig. 2A) (15). The IC50 is the concentration of drug required to inhibit 48-hr cell growth by compared to untreated controls.…”

Section: Resultsmentioning

confidence: 99%

“…Drug cytotoxicity and IC50 values were determined in a 48-hr growth inhibition assay, also as described previously (15). The IC50 is the concentration of drug required to inhibit cell growth by 50%o compared to untreated controls.…”

mentioning

confidence: 99%

Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance.

Pearce

Safa²,

Bach³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

210

108

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“…Meador et al (1987) found some effect of CsA at 1 ,tg ml-' in drug sensitive Ehrlich ascites carcinoma and murine hepatoma 129 cell lines, although this effect was small compared to our experiments. Twentyman et al (1987) (Inaba & Maruyama, 1988) and with the calcium channel blocker Verapamil (Beck et al, 1986). …”

Section: Discussionmentioning

confidence: 99%

Overcoming multidrug resistance in Chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and non-immunosuppressive derivatives

Gavériaux

Boesch²,

Boelsterli³

et al. 1989

Br J Cancer

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Reversal of Vinca alkaloid resistance but not multiple drug resistance in human leukemic cells by verapamil

Cited by 20 publications

References 0 publications

Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil.

Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil.

Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance.

Overcoming multidrug resistance in Chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and non-immunosuppressive derivatives

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