The bisindolylmaleimide protein kinase C inhibitor, Ro 32-2241, reverses multidrug resistance in KB tumour cells

Ro 32-2241 is a bisindolylmaleimide that selectively inhibits protein kinas e C (PKC) as compared with other protein kinases. Experiments were carried out to examine its potential as a multidrug resistance-reversing agent. Ro 32-2241 inhibited efflux, and increased accumulation, of [H-3]-daunomycin i n multidrug-resistant (MDR) KB-8-5 and KB-8-5-11 cells and had no effect on drug-sensitive KB-3-1 cells. Ro 32-2241 completely reversed the doxorubici n resistance of KB-8-5 and KB-8-5-11 cells, showing no effect on the sensit ivity of drug-sensitive KB-3-1 cells. The potency of Ro 32-2241 was compara ble with that of cyclosporin A and better than that of verapamil, known mod ulators of multidrug resistance. Ro 32-2241 also completely reversed the ta xol resistance of KB-8-5 cells and partially reversed the resistance of KB- 8-5-11 cells. Vinblastine resistance was also partially reversed. Mechanist ic experiments were carried out to determine whether Ro 32-2241 interacted with P-glycoprotein (Pgp) directly. Increased efflux of [C-14]-Ro 32-2241 w as seen with the more resistant KB-8-5-11 cells (although the percentage ef fluxed was very low as compared with [H-3]-daunomycin), suggesting that Po 32-2241 can act as a substrate for Pgp. Direct interaction of Ro 32-2241 wi th Pgp was confirmed by demonstration that it inhibited binding of [H-3]-az idopine to Pgp in KB-8-5-11 membranes. In conclusion, Ro 32-2241, acting di rectly on Pgp (rather than, or in addition to, an effect on PKC), is effect ive in reducing or reversing resistance to doxorubicin, taxol and vinblasti ne in human tumour cells with a clinically relevant degree of MDR. However, results of in vivo experiments conducted to investigate the effects of Ro 32-2241 on resistance to doxorubicin suggest that it may not be possible to achieve sufficiently high levels of Ro 32-2241 in vivo to modulate MDR.