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首页> 外文期刊>The Internet Journal of Pharmacology >Phosphodiesterase as a novel target in Cancer Chemotherapy
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Phosphodiesterase as a novel target in Cancer Chemotherapy

机译：磷酸二酯酶作为癌症化学疗法的新靶标

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The Phosphodiesterase inhibitors have been used for the treatment of non-malignant conditions like asthma, pulmonary hypertension and erectile dysfunction etc, but the recent research suggests that they have great therapeutic value in the adjunctive therapy of Cancer. This article reviews the various substances elevating the intracellular cyclic AMP levels such as cAMP analogues and Phosphodiesterases inhibitors to induce apoptosis selectively in a variety of cancer cell lines with out affecting the normal cells. Their usefulness in the adjunctive therapy of cancer is explained. Introduction Research aimed for treatment of cancer had been the focus of many industries and academic groups since last two decades. Besides radiation therapy and surgery, chemotherapy is the major modality for the treatment of cancer. But most of the chemotherapeutic agents exhibit different ranges of toxicity because they are administered at their maximum tolerated doses. But with the use of the drugs that elevate the intracellular cyclic AMP levels such as cAMP analogues and Phosphodiesterase inhibitors, we can achieve the therapeutic target just above the minimum effective concentration of the currently used anti-cancer drugs, thus avoiding the potential adverse effects. This improves the patient compliance too. In this article, an attempt has been made in elucidating the role of raised levels of cAMP in inducing apoptosis by agents such as cAMP analogues and Phosphodiesterase inhibitors. The recent advances of research on the potential role of Phosphodiesterase inhibitors to selectively induce apoptosis in various experimental models have been explained.Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3'-5'-cyclic adenosine monophosphate) is a molecule that is important in many biological processes. cAMP is derived from adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms. It is synthesised from ATP by adenylyl cyclase which is located at the cell membranes. In humans, cAMP works by activating protein kinase A (PKA, also known as cAMP-dependent protein kinase). Cyclic adenosine monophosphate (cAMP) has a dual effect i.e., proliferation and differentiation processes in cells. The main target of cAMP action in the cell is cAMP-dependent protein kinase, which may exist as two different isozymes, designated as type I (PKA-I) and type II (PKA-II). PKA-I acts as a positive growth effector, whereas PKA-II inhibits cell division 1 . Cyclic AMP as a tool to combat cancer Cyclic AMP is a positive intracellular signal for cell proliferation in many differentiated cells. But in many tumor cells it is a negative messenger for proliferation, showing a much lower basal level than in normal cells 2 . The lowest concentration of cyclic AMP found to affect cell growth was o.1 mM & at a concentration of 0.5mM it arrested cell multiplication after 24 h in monolayer cultures of human liver cells 3 . Additions of high, nonphysiological concentrations (10 -5 M to 10 -3 M) of cyclic AMP suppress the induction of DNA synthesis after serum addition in quiescent mouse fibroblasts 4 . Selective toxicity of cAMP towards Cancer cells In malignant tissue, the concentration of cyclic AMP is lower in cells transformed in vitro by oncogenic viruses than in untransformed cells, and is lower in certain tumours grown in vivo than in the corresponding normal tissue 5 .The growth of four tumorigenic cell lines (Fl amnion, HEp-2, HeLa(line 229) and strain L (NCTC clone 929) was inhibited from 70 to 89% by adenosine 3' , 5'-cyclic monophosphate (0.3 mM) whereas a non-malignant cell line (WI-38) was affected only slightly (13%). Guanosine 3', 5'-cyclic monophosphate and quanosine 2', 3'-cyclic monophosphate) did not show selectivity; they inhibited the tumorigenic strains and the Wl-38 cell line. This shows that cAMP growth inhibition is selective towards tumorigenic cell lines 6 .In malignant cells, exogenous cyclic AMP or agents tha
机译：磷酸二酯酶抑制剂已被用于治疗非恶性疾病，例如哮喘，肺动脉高压和勃起功能障碍等，但是最近的研究表明它们在癌症的辅助治疗中具有巨大的治疗价值。本文综述了提高细胞内环AMP含量的各种物质，例如cAMP类似物和磷酸二酯酶抑制剂，以选择性诱导多种癌细胞系中的细胞凋亡而不影响正常细胞。解释了它们在癌症辅助治疗中的有用性。简介自最近二十年来，针对癌症的治疗研究一直是许多行业和学术团体的关注重点。除放射疗法和外科手术外，化学疗法是治疗癌症的主要方式。但是大多数化学治疗剂表现出不同的毒性范围，因为它们以其最大耐受剂量给药。但是，通过使用可提高细胞内环AMP含量的药物（如cAMP类似物和磷酸二酯酶抑制剂），我们可以达到略高于当前使用的抗癌药物最低有效浓度的治疗目标，从而避免了潜在的不良影响。这也改善了患者的依从性。在本文中，已尝试阐明升高水平的cAMP在通过诸如cAMP类似物和磷酸二酯酶抑制剂等试剂诱导细胞凋亡中的作用。解释了磷酸二酯酶抑制剂在多种实验模型中选择性诱导细胞凋亡的潜在作用的最新研究进展。环腺苷单磷酸（cAMP，环AMP或3'-5'-环腺苷单磷酸）是一种重要的分子。许多生物学过程。 cAMP源自三磷酸腺苷（ATP），用于许多不同生物中的细胞内信号转导。它是由ATP通过位于细胞膜上的腺苷酸环化酶合成的。在人类中，cAMP通过激活蛋白激酶A（PKA，也称为cAMP依赖性蛋白激酶）起作用。环状单磷酸腺苷（cAMP）具有双重作用，即细胞中的增殖和分化过程。细胞中cAMP作用的主要靶点是cAMP依赖性蛋白激酶，它可以两种不同的同功酶形式存在，分别称为I型（PKA-I）和II型（PKA-II）。 PKA-I发挥积极的生长效应，而PKA-II抑制细胞分裂1。循环AMP作为对抗癌症的工具循环AMP是许多分化细胞中细胞增殖的阳性细胞内信号。但是在许多肿瘤细胞中，它是增殖的阴性信使，其基础水平比正常细胞低得多2。发现影响细胞生长的环状AMP的最低浓度为o.1 mM，在浓度为0.5mM的情况下，它在人肝细胞的单层培养物中24 h后阻止细胞增殖3。高，非生理浓度（10 -5 M到10 -3 M）的环状AMP的添加抑制了静态小鼠成纤维细胞中血清添加后DNA合成的诱导4。 cAMP对癌细胞的选择性毒性在恶性组织中，在由致癌病毒体外转化的细胞中，环状AMP的浓度低于未转化的细胞，并且在体内生长的某些肿瘤中，环状AMP的浓度也低于相应的正常组织5。腺苷3'，5'-环一磷酸（0.3 mM）将四种致瘤细胞系（F1羊膜，HEp-2，HeLa（系229）和L株（NCTC克隆929）抑制了70％至89％ -恶性细胞株（WI-38）仅受到轻微影响（13％），鸟苷3'，5'-环一磷酸和quanosine 2'，3'-环一磷酸）没有显示选择性。它们抑制了致瘤菌株和W1-38细胞系。这表明cAMP的生长抑制对肿瘤细胞系6具有选择性。在恶性细胞中，外源性环状AMP或药物tha

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