KT-5720 REVERSES MULTIDRUG-RESISTANCE IN VARIANT S49 MOUSE LYMPHOMA-CELLS TRANSDUCED WITH THE HUMAN MDR1 CDNA AND IN HUMAN MULTIDRUG-RESISTANT CARCINOMA-CELLS

T-25-Adh cells, cell variants derived from S49 mouse lymphoma, were transduced with a retrovirus containing the human MDR1 cDNA. The resultant cells (HU-1) are cross-resistant to colchicine, doxorubicin, vinblastine and actinomycin D, and their resistance to colchicine is reversed by verapamil. HU-1 cells were used to screen several protein kinase modulators for their ability to reverse multidrug resistance. Among the tested indole carbazole (K-252a) family of protein kinase inhibitors, only the antibiotic alkaloid KT-5720 (9-n-hexyl derivative of K-252a) could overcome the multidrug resistance of HU-1 cells and KB-V1 human carcinoma cells. Since other protein kinase A, C and G modulators did not reverse multidrug resistance in the tested multidrug-resistant cells, the chemosensitising activity of KT-5720 on these cells is apparently independent of its kinase inhibitory effects. Since KT-5720 fully reversed multidrug resistance at non-toxic concentrations, it might be a candidate for clinical chemosensitisation in combination chemotherapy.