Reversal of vinblastine resistance by a new staurosporine derivative, NA-382, in P388ADR cells

doi:10.1016/0304-3835(92)90079-B

Cancer Letters

Volume 64, Issue 2, 15 June 1992, Pages 177-183

https://doi.org/10.1016/0304-3835(92)90079-B Get rights and content

Abstract

Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), $Ca^{2+} phospholipid$ dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of staurosporine. NA-382 was less toxic to P388 cells and at a noncytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 ( $P388 ADR$ ) cells without influence on the effect of VBL on the parental $P388 S$ cells. However, the cytotoxicity of staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in $P388 ADR$ with higher potency than staurosporine. Both compounds inhibited the photolabeling of [³H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.

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Reversal of vinblastine resistance by a new staurosporine derivative, NA-382, in P388ADR cells

Abstract

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Leukemia Res.

J. Biol. Chem.

Cancer Lett.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Most drugs that reverse multidrug resistance also inhibit photoaffinity labeling of P-glycoprotein by a vinblastine analog

Mol. Pharmacol.

Reversal of vinblastine resistance by a new staurosporine derivative, NA-382, in $P388 ADR$ cells