Phosphodiesterase inhibitors as anti-cancer drugs
Phosphodiesterase inhibitors as anti-cancer drugs
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DOI：
10.1016/j.bcp.2004.05.026
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发表时间：
2004-09-15
影响因子：
5.8
通讯作者：
Amsterdam, A
中科院分区：
文献类型：
--
作者：
Hirsh, L;Dantes, A;Amsterdam, A
众所周知，高水平的细胞内cAMP可以在体外有效地杀死癌细胞。不幸的是，升高cAMP的物质，如福斯克林、8-溴-cAMP、8-氯-cAMP、单丁基或二丁基cAMP，由于其高细胞毒性，不建议用作抗癌药物。相比之下，磷酸二酯酶的阻滞剂，如茶碱和氨茶碱，可以升高细胞内cAMP，通常被用作抗哮喘药物，血液中浓度达到10-20马克杯/毫升。我们测试了茶碱和氨茶碱单独或与常见抗癌药物如顺铂和吉西他滨（gemzar）联合诱导细胞死亡的有效性。我们研究了这些药物组合在诱导来自人类卵巢癌、前列腺癌和肺癌的多种癌细胞系以及由SV40和Ras癌基因转化的颗粒细胞系中细胞死亡的作用。茶碱在20-25马克杯/毫升浓度下可诱导细胞中度死亡，而氨茶碱在此浓度下无效。茶碱（15-25 ng/ml）在所有四种代表性细胞系中发现与吉西他滨或顺铂协同作用诱导程序性细胞死亡，这使得顺铂和吉西他滨的有效剂量减少了2-3倍。茶碱在诱导细胞凋亡中的作用与降低细胞内Bcl2水平有关。这种减少与茶碱和联合药物治疗诱导的细胞凋亡程度成正比。因此，我们建议将茶碱作为一种潜在的抗癌药物与其他化疗药物联合使用。筛选其他没有严重毒性的磷酸二酯酶阻滞剂，可能会为改善化疗癌症治疗提供可能性，减少不良副作用。使用茶碱作为抗癌药物的临床试验目前正在肺癌患者中进行。(C) 2004爱思唯尔公司版权所有。
It is well known that high intracellular levels of cAMP can effectively kill cancer cells in vitro. Unfortunately substances elevating cAMP such as forskolin, 8-bromo-cAMP, 8-chloro-cAMP, monobutiryl or dibutiryl cAMP are not recommended to be used as anti-cancer drugs because of their high cytotoxicity. In contrast blockers of phosphodieterases such as theophylline and aminophylline, which could elevate intracellular cAMP, are commonly used as anti-asthma drugs reaching concentrations in the blood of 10-20 mug/ml. We tested the effectiveness of theophylline and aminophylline to induce cell death alone or in combination with common anti-cancer drugs such as cisplatin and gemcitabine (gemzar). We examined such drug combinations in the induction of cell death in a variety of carcinoma cell lines derived from human ovarian, prostate and lung cancer and in granulosa cell line transformed by SV40 and Ras oncogene. While theophylline could induce moderate cell death alone, at 20-25 mug/ml concentrations, aminophylline was ineffective at this concentration. Theophylline (at 15-25 ng/ml) was found in all four representative cell lines to synergize with gemcitabine or cisplatin to induce programmed cell death, which permits a reduction in the effective doses of cisplatin and gemcitabine by 2-3-fold. The effect of theophylline in induction of apoptosis involved reduction of intracellular levels of Bcl2. Such a reduction was proportional to the extent of apoptosis induced by theophylline as well as by the combined drug treatments. Therefore, we propose that theophylline should be considered as a potential anti-cancer drug in combination with other chemotherapeutic drugs. Screening of other phosphodiesterase blockers, which are not severely toxic, could open a possibility to improved chemotherapeutic cancer treatments with reduced undesired side-effects. A clinical trial, using theophylline as an anti-cancer drug, is currently being conducted in lung cancer patients. (C) 2004 Elsevier Inc. All rights reserved.