MODULATING MULTIDRUG-RESISTANCE THROUGH INHIBITING OF PROTEIN-KINASE-C ACTIVITY BY PHENOTHIAZINES

In the present study, actions of phenothiazines(PTZ) in reversing mult idrug resistance (MDR) and inhibiting PKC activity were investigated. It was found that the three PTZs caused 2.49, 36.58 and 75.78 fold rev ersal of K562/AO2 MDR cells resistant to adriamycin, respectively, whi le the chemosensitizer verapamil caused 40 fold reversal in the same c ondition, indicating that PTZ11 is a novel reversal agent of MDR and a potential chemotherapeutic reagent for tumor therapy. PKC activity an alysis in the presence of PTZs showd that PTZ6 and PTZ11 inhibited rat brain protein kinase C activity in a manner of dose-dependent. The lc ,, values were (489.77 +/- 31.4) and (113 +/- 9.64) mu mol/L, respecti vely. PTZ7 had no inhibition on PKC activity. Further study showed tha t PTZ11 could reduce PMA-mediated activation of PKC in a manner of dos e-dependent, suggesting that PTZ11 might compete for the high-affinity phorbol ester binding site within PKC molecule. Recently, an X-ray st ructure of PMA in complex with PKC Cys2 activator-binding domain was s olved. We therefore decided to explore the possible binding model of P TZ11 with PKC molecule using SYBYL 6.02 program. It was shown that the binding site of PTZ11 with PKC molecule partially overlapped with tha t of PMA, providing for the first time new data for designing PKC inhi bitors and MDR reversal drugs.