COMPARISON OF STAUROSPORINE AND 4 ANALOGS - THEIR EFFECTS ON GROWTH, RHODAMINE-123 RETENTION AND BINDING TO P-GLYCOPROTEIN IN MULTIDRUG-RESISTANT MCF-7 ADR CELLS/

The potent kinase inhibitor staurosporine and its protein kinase C (PK C)-selective analogue CGP 41251 are known to sensitise cells with the multidrug resistance (MDR) phenotype mediated by P-glycoprotein (P-gp) to cytotoxic agents. Here Four PKC-selective staurosporine RO 31 8220 and GF 109203X, were compared with staurosporine in terms of their MD R-reversing properties and their susceptibility towards P-gp-mediated drug efflux from MCF-7/Adr cells. Staurosporine was the most potent an d the bisindolylmaleimides RO 31 8220 and GF 109203X the least potent cytostatic agents. When compared with MCF-7 wild-type cells, MCF-7/Adr cells were resistant towards the growth-arresting properties of RO 31 8220 and UCN-01, with resistance ratios of 12.6 and 7.0 respectively. This resistance could be substantially reduced by inclusion oi the P- gp inhibitor reserpine. The ratios For GF 109203X, staurosporine and C GP 41251 were 1.2, 2.0 and 2.9 respectively, and they were hardly affe cted by reserpine. These results suggest that RO 31 8220 and UCN-01 ar e avidly transported by P-gp but that the other compounds are not. Sta urosporine and CGP 41251 at 10 and 20 nM, respectively, decreased effl ux of the P-gp probe rhodamine 123 (R123) from MCF-7/Adr cells, wherea s RO 31 8220 and GF 109203X at 640 nM were inactive. CGP 41251 was the most effective and GF 109203X the least effective inhibitor of equili brium binding of [H-3]vinblastine to its specific binding sites, proba bly P-gp, in MCF-7/Adr cells. Overall, the results imply that for this class of compound the structural properties that determine susceptibi lity towards P-gp-mediated substrate transport are complex. Comparison with ability to inhibit PKC suggests that the kinase inhibitors affec t P-gp directly and not via inhibition of PKC. Among these compounds C GP 41251 was a very potent MDR-reversing agent with high affinity for P-gp and least affected by P-gp-mediated resistance, rendering it an a ttractive drug candidate for clinical development.