P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A

  • Authors:
    • W Ise
    • M Heuser
    • K Sanders
    • J Beck
    • V Gekeler
  • View Affiliations

  • Published online on: May 1, 1996     https://doi.org/10.3892/ijo.8.5.951
  • Pages: 951-956
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Abstract

A series of different human MDR (multidrug-resistant) cell lines including a HeLa-MDR1 transfectant which exhibit high overexpression of the MDR1/P-glycoprotein gene, but no enhanced expression of the MRP (multidrug resistance associated protein) gene, showed different ratios of relative resistances to the taxanes taxol and taxotere. Using these cell lines the chemosensitizing efficacies of several structurally different chemosensitizers, i.e. the dihydropyridine dexniguldipine-HC1 (B8509-035), its main pyridine metabolite M1 (B8909-008), the cyclic peptide cyclosporin A, or the phenylalkylamine dexverapamil-HCl, were examined applying a 72 h tetrazolium based colorimetric MTT-assay, or a 96 h sulforhodamine B assay. Remarkably, we observed in some instances that the modulating efficacy of a particular chemosensitizer was strongly dependent on the cell line used for experimentation. Thus, dexniguldipine-HCl efficiently modulated taxane resistances of the ovarian carcinoma MDR cell line 2780AD in the submicromolar concentration range, whereas cyclosporin A and the other chemosensitizers were rather ineffective. Dexniguldipine-HCl or cyclosporin A, however, both showed a similarly strong modulating activity on the HeLa-MDR1 transfectant in clear contrast to the effects observed using the pyridine B8909-008, or dexverapamil-HCl, respectively, at the same final concentrations. Our results point to additional, as yet unidentified factors beyond the expression levels of P-glycoprotein which could contribute to the susceptibility of MDR cells to a combined treatment using taxanes and different chemosensitizing compounds. This result appears to be important considering the clinical application of chemosensitizers for combination therapy of tumors of different origin.

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May 1996
Volume 8 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Ise W, Heuser M, Sanders K, Beck J and Gekeler V: P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A. Int J Oncol 8: 951-956, 1996
APA
Ise, W., Heuser, M., Sanders, K., Beck, J., & Gekeler, V. (1996). P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A. International Journal of Oncology, 8, 951-956. https://doi.org/10.3892/ijo.8.5.951
MLA
Ise, W., Heuser, M., Sanders, K., Beck, J., Gekeler, V."P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A". International Journal of Oncology 8.5 (1996): 951-956.
Chicago
Ise, W., Heuser, M., Sanders, K., Beck, J., Gekeler, V."P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A". International Journal of Oncology 8, no. 5 (1996): 951-956. https://doi.org/10.3892/ijo.8.5.951