A newly synthesized bifunctional inhibitor, CKA1083, enhances adriamycin activity against human ovarian carcinoma cells.
BACKGROUND
A newly synthesized drug, CKA1083 ((S)-N-[2-(4-benzyloxy-carbonylpiperazinyl)-1-(P-methoxybenzyl) ethyl]-N-methyl-N(5-isoquinolinesulfonamide)), has the same glutathione-S-transferase (GST)-binding site structure as W-77, a bifunctional inhibitor that enhances the cytotoxicity of Adriamycin for human ovarian carcinoma cells. We examined the effects of CKA1083 on the cytotoxicity of Adriamycin and the resistance of human ovarian carcinoma cells to this drug.


METHODS
We used GST-pi transfected cells and Adriamycin-sensitive or -resistant cells of human ovarian carcinoma. GST-pi activity, the intracellular Adriamycin content, and the cytotoxicity of Adriamycin in these cell lines in the presence or absence of CKA1083 were measured and compared to the findings obtained with W-77 or verapamil.


RESULTS
CKA1083 inhibited GST-pi activity in an uncompetitive manner and more strongly than W-77. It enhanced the cytotoxicity of Adriamycin for GST-pi transfected cells by about 3-times. Further, CKA1083 increased the intracellular Adriamycin content about 3-fold in two Adriamycin-resistant cell lines (NOS2AR and NOS3AR). CKA1083 (10 microM) reduced the IC50 of Adriamycin to 1/38 in NOS2AR cells and 1/21 in NOS3AR cells, and overcame Adriamycin resistance more effectively than both W-77 and verapamil.


CONCLUSIONS
CKA1083 enhanced the antitumor effect of Adriamycin more than W-77 by inhibiting both GST activity and P-glycoprotein.
Maeda
O
O
Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Japan.
Kikkawa
F
F
Tamakoshi
K
K
Obata
N H
NH
Mizuno
K
K
Suganuma
N
N
Tomoda
Y
Y
Kuzuya
K
K
Ishikawa
T
T
Hidaka
H
H
D000970:Antineoplastic Agents / Q000633:toxicity*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000633:toxicity*; D007700:Kinetics; D010051:Ovarian Neoplasms; D010879:Piperazines / Q000737:chemistry / Q000633:toxicity; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013449:Sulfonamides / Q000737:chemistry / Q000633:toxicity; D014162:Transfection; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000970:Antineoplastic Agents; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase; D007546:Isoquinolines; D010879:Piperazines; D011994:Recombinant Proteins; D013449:Sulfonamides; D014700:Verapamil; C107002:CKA1083; C080983:W 77; D000096926:Benzenesulfonamides