Inhibition of multidrug resistance by a new staurosporine derivative, NA-382, in vitro and in vivo
Miyamoto, K.; Inoko, K.; Wakusawa, S.; Kajita, S.; Hasegawa, T.; Takagi, K.; Koyama, M.
Cancer Research 53(7): 1555-1559
1993
ISSN/ISBN: 0008-5472 PMID: 8095855 Document Number: 405908
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 Ca-2+/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 Ca-2+/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 bv Ca-2+/phospholipid-dependent protein kinase inhibitory action.