Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents.
Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents.
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1,2-萘醌对人类肿瘤细胞生长的影响，且与其他抗癌药物缺乏交叉耐药性。
DOI：
10.1097/00001813-199806000-00011
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发表时间：
1998
影响因子：
2.3
通讯作者：
Marton,LJ
中科院分区：
文献类型：
--
作者：
Dolan,ME;Frydman,B;Thompson,CB;Diamond,AM;Garbiras,BJ;Safa,AR;Beck,WT;Marton,LJ
研究了人类肿瘤和大鼠前列腺肿瘤细胞对一系列萘醌类化合物的敏感性，包括03B2Lapachone和dunnlone家族的三环化合物以及4-烷氧基1,2 -萘醌类化合物。为了更好地了解1,2 -萘醌类药物的细胞毒性机制，研究了多种耐药机制的作用，包括p -糖蛋白、多药耐药相关蛋白、谷胱甘肽（GSH）及其相关酶、拓扑异构酶活性的改变以及控制凋亡基因（bcl-2和bcl-x L）的过表达。MCF7细胞对萘醌类药物最敏感，ic50值为1.1 ~ 10.8 U03BCM 1，而HT29人结肠、A549人肺、CEM白血病和AT3的ic50值为2.5 ~ bbb32 U03BCM。1大鼠前列腺癌细胞。对阿霉素（ADR）产生耐药性的MCF7 ADR细胞对三环1,2 -萘醌类药物表现出交叉耐药性。通过p -糖蛋白机制的药物外排被排除为对1,2 -萘醌耐药的机制，因为表达高水平p -糖蛋白的KB-V1细胞和KB-3.1亲本系对这些化合物同样敏感。在耐药细胞中发现的三环萘醌的任何抗性似乎都与谷胱甘肽氧化还原循环有关，并且可以通过暴露于丁胺亚胺或通过将三环衍生物的结构改变为4-烷氧基1,2 -萘醌来规避。1,2 -萘醌类化合物分别对耐替尼普苷和merbarone的CEM/VM-1和CEM/M70-B1细胞具有细胞毒性。此外，过表达bcf-2或bcf-xL蛋白的细胞与对照细胞一样对1,2 -萘醌敏感。由于它们在耐药细胞中的有效性，这些药物似乎有望成为有效的化疗药物
The sensitivity of human tumor and rat prostate tumor cells to a series of naphthoqulnones, including tricyclic compounds of the 03B2Lapachone and dunnlone families as well as 4-alkoxy-1, 2-naphthoquinones, was evaluated. To better understand the mechanism of cytotoxicity of 1, 2-naphthoquinones, the roles of various resistance mechanisms including P-glycoprotein, multidrug resistant associated protein, glutathione (GSH) and related enzymes, altered topoisomerase activity, and overexpression of genes that control apoptosls (bcl-2 and bcl-x L were studied. MCF7 cells were most sensitive to the naphthoquinones with IC 50 values ranging from 1.1 to 10.8 U03BCM 1 as compared to 2.5 to> 32 U03BCM for HT29 human colon, A549 human lung, CEM leukemia and AT3. 1 rat prostate cancer cells. MCF7 ADR cells, selected for resistance to adriamycin (ADR), displayed cross-resistance to the tricyclic 1, 2-naphthoquinones. Drug efflux via a P-glycoprotein mechanism was ruled out as a mechanism of resistance to 1, 2-naphthoquinones, since KB-V1 cells expressing high levels of P-glycoprotein and the KB-3.1 parent line were equally sensitive to these compounds. Any resistance of the tricyclic naphthoquinones noted In ADRresistant cells appeared to relate to the GSH redox cycle and could be circumvented by exposure to buthlonine sulfox-Imine or by changing the structure from a tricyclic derivative to a 4-alkoxy-1, 2-naphthoquinone. The 1, 2-naphthoquinones were found to be cytotoxic against CEM/VM-1 and CEM/M70-B1 cells that were selected for resistance to teniposide or merbarone, respectively. In addition, cells overexpressing bcf-2 or bcf-xL proteins were as sensitive to 1, 2-naphthoquinones as were control cells. Because of their effectiveness In drug-resistant cells, these agents appear to hold promise as effective chemotherapeutic agents