一种新合成的双功能抑制剂CKA1083增强了阿霉素对人卵巢癌细胞的活性。

A newly synthesized bifunctional inhibitor, CKA1083, enhances adriamycin activity against human ovarian carcinoma cells.

作者信息

Maeda O, Kikkawa F, Tamakoshi K, Obata N H, Mizuno K, Suganuma N, Tomoda Y, Kuzuya K, Ishikawa T, Hidaka H

机构信息

Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Japan.

出版信息

Anticancer Res. 1997 May-Jun;17(3C):1985-92.

PMID:9216655

Abstract

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.

MATERIALS AND 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.

摘要

背景

一种新合成的药物CKA1083（(S)-N-[2-(4-苄氧羰基哌嗪基)-1-(对甲氧基苄基)乙基]-N-甲基-N(5-异喹啉磺酰胺)）具有与W-77相同的谷胱甘肽-S-转移酶（GST）结合位点结构，W-77是一种双功能抑制剂，可增强阿霉素对人卵巢癌细胞的细胞毒性。我们研究了CKA1083对阿霉素细胞毒性以及人卵巢癌细胞对该药物耐药性的影响。

材料与方法

我们使用了GST-π转染细胞以及人卵巢癌的阿霉素敏感或耐药细胞。测量了在有或没有CKA1083存在的情况下这些细胞系中GST-π活性、细胞内阿霉素含量以及阿霉素的细胞毒性，并与用W-77或维拉帕米获得的结果进行比较。

结果

CKA1083以非竞争性方式抑制GST-π活性，且比W-77更强。它使阿霉素对GST-π转染细胞的细胞毒性增强了约3倍。此外，CKA1083使两种阿霉素耐药细胞系（NOS2AR和NOS3AR）中的细胞内阿霉素含量增加了约3倍。CKA1083（10μM）使NOS2AR细胞中阿霉素的IC50降至1/38，在NOS3AR细胞中降至1/21，并且比W-77和维拉帕米更有效地克服了阿霉素耐药性。