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.
Galski
H
H
Unit of Molecular Biology and Genetic Engineering, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel.
Lazarovici
P
P
Gottesman
M M
MM
Murakata
C
C
Matsuda
Y
Y
Hochman
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D002227:Carbazoles; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D002227:Carbazoles; D018076:DNA, Complementary; D007211:Indoles; D011758:Pyrroles; C057416:KT 5720; D011493:Protein Kinase C