This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miyamoto, K.-i. Articles by Koyama, M. Search for Related Content PubMed PubMed Citation Articles by Miyamoto, K.-i. Articles by Koyama, M.

Inhibition of Multidrug Resistance by a New Staurosporine Derivative, NA-382, in Vitro and in Vivo¹

Research Laboratory for Development of Medicine, School of Pharmacy, Hokuriku University, Kanazawa 920-11, Japan [K-i. M., K. I., S. W.]; Nagoya University School of Medicine, Nagoya 466, Japan [S. K., T. H., K. T.]; and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama 222, Japan [M. K.]

The effects of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382), on multidrug resistance in tumor cells were investigated. Protein kinase-inhibitory activity of NA-382 was lower but more selective to Ca²⁺/phospholipid-dependent protein kinase than that of staurosporine. NA-382 at noncytotoxic concentrations effectively reversed in vitro multidrug resistance of Adriamycin-resistant P388 (P388/ADR) cells, without influencing the drug sensitivity of sensitive P388 cells. NA-382 inhibited extrusion of vinblastine (VBL) and increased intracellular accumulation of VBL, more in P388/ADR cells than in sensitive P388 cells, with higher potency than staurosporine. This compound also reduced VBL resistance of other multidrug-resistant cell lines, AH66 and K562/ADR, by inhibiting VBL efflux and promoting VBL accumulation. NA-382 also dose dependently potentiated the effects of VBL and Adriamycin in P388/ADR-bearing mice. The toxicity of staurosporine was too high to use the combination with VBL in vitro and in vivo. NA-382 accumulated VBL in P388/ADR cells even after desensitization of Ca²⁺/phospholipid-dependent protein kinase by treatment with 12-O-tetradecanoylphorbol-13-acetate for 18 h, while being suppressed by 12-O-tetradecanoylphorbol-13-acetate added simultaneously or shortly before NA-382. Both staurosporine and NA-382 inhibited the photolabeling of [³H]azidopine on M_r 140,000 P-glycoprotein in the plasma membrane from P388/ADR cells. These results indicate that this new staurosporine analogue, NA-382, reverses multidrug resistance by directly inhibiting the drug binding to P-glycoprotein, but not by Ca²⁺/phospholipid-dependent protein kinase inhibitory action.

¹ Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed.

Received 7/27/92. Accepted 1/27/93.

This article has been cited by other articles:

				K. P. Gupta, N. E. Ward, K. R. Gravitt, P. J. Bergman, and C. A. O'Brian Partial Reversal of Multidrug Resistance in Human Breast Cancer Cells by an N-Myristoylated Protein Kinase C-alpha Pseudosubstrate Peptide J. Biol. Chem., January 26, 1996; 271(4): 2102 - 2111. [Abstract] [Full Text] [PDF]

				C. W. Sachs, A. R. Safa, S. D. Harrison, and R. L. Fine Partial Inhibition of Multidrug Resistance by Safingol Is Independent of Modulation of P-glycoprotein Substrate Activities and Correlated with Inhibition of Protein Kinase C J. Biol. Chem., November 3, 1995; 270(44): 26639 - 26648. [Abstract] [Full Text] [PDF]