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首页> 外文期刊>Advances in enzyme regulation >Amplification of signal transduction capacity and down-regulation by drugs.
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Amplification of signal transduction capacity and down-regulation by drugs.

机译：信号转导能力的增强和药物的下调。

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Recent work in this Laboratory showed increased activity of PI 4-kinase, PIP kinase and PLC in various cancer cells, indicating a stepped-up capacity for signal transduction. This elevated potential was paralleled with increased concentration of the end product of signal transduction, IP3. Current investigations showed that in normal cells the activities of the specific phosphatases (which degrade PIP2 and PIP and oppose those of the synthetic enzymes) were 4 to 5 orders of magnitude higher than those of the synthetic kinases. In hepatoma cells the specific phosphatase activities markedly decreased. Thus, in cancer cells the marked elevations in activities of the synthetic enzymes were opposed by a reduction in the activities of the degradative specific phosphatases. This enzymic imbalance is responsible, in part at least, for the elevated capacity of signal transduction and IP3 concentration. Since the enzymic activities measured were proportionate with time elapsed and amount of enzyme added, the alterations in activities should reflect changes in enzyme amounts. These alterations indicate a reprogramming of gene expression which should confer selective advantages to the cancer cells, marking out the elevated synthetic enzyme activities as potentially sensitive targets for drug treatment. We showed earlier that tiazofurin, which curtailed the biosynthesis of enzymes with short half-lives such as PI and PIP kinases, down-regulated signal transduction and brought down IP3 concentration. Quercetin and genistein chiefly inhibited PI-4 kinase and PIP kinase, respectively, and as a result reduced IP3 concentration in cancer cells. Current studies reveal that tiazofurin with quercetin, tiazofurin with genistein, and quercetin with genistein were synergistic in killing human cancer cells and in reducing signal transduction activity. In estrogen receptor-negative MDA-MB-435 human breast carcinoma cells which have elevated signal transduction activity, tamoxifen caused IC50S for growth inhibition and cytotoxicity of 12 and 0.7 microM, respectively. When tiazofurin was added to breast carcinoma cells, followed 12 hr later by tamoxifen, synergism was observed in growth inhibition, in clonogenic assays and in the reduction of IP3 concentration. The synergistic action of tiazofurin and tamoxifen and the other synergistic drug interactions outlined above may have implications in the clinical treatment of neoplasias.
机译：该实验室的最新工作表明，PI 4激酶，PIP激酶和PLC在各种癌细胞中的活性增强，表明信号转导能力增强。这种升高的电位与信号转导终产物IP3浓度的增加平行。当前的研究表明，在正常细胞中，特定磷酸酶的活性（降解PIP2和PIP并与合成酶相反）比合成激酶的活性高4至5个数量级。在肝癌细胞中，特定的磷酸酶活性明显降低。因此，在癌细胞中，合成酶活性的显着升高被降解特异性磷酸酶的活性降低所抵消。这种酶的失衡至少部分地是导致信号转导能力和IP3浓度升高的原因。由于测得的酶活性与经过的时间和添加的酶量成正比，因此活性的变化应反映酶量的变化。这些改变指示基因表达的重编程，其应赋予癌细胞选择性的优势，标志着合成酶活性的升高是药物治疗的潜在敏感靶标。我们较早地表明，噻唑林可以减少半衰期短的酶（如PI和PIP激酶）的生物合成，下调信号转导并降低IP3浓度。槲皮素和染料木黄酮分别主要抑制PI-4激酶和PIP激酶，因此降低了癌细胞中IP3的浓度。当前的研究表明，噻唑呋林与槲皮素，噻唑呋林与染料木黄酮以及槲皮素与染料木黄酮在杀死人类癌细胞和降低信号转导活性方面具有协同作用。在具有升高的信号转导活性的雌激素受体阴性的MDA-MB-435人乳腺癌细胞中，他莫昔芬导致IC50S的生长抑制和细胞毒性分别为12和0.7 microM。当将噻唑呋林添加到乳腺癌细胞中，然后在12小时后加入他莫昔芬时，在生长抑制，克隆形成测定和IP3浓度降低中观察到协同作用。噻唑呋林和他莫昔芬的协同作用以及上面概述的其他协同药物相互作用可能对瘤形成的临床治疗有影响。

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