Fecker L F, Stockfleth E, Nindl I, Ulrich C, Forschner T, Eberle J
Department of Dermatology, Charité, Skin Cancer Center Charité, University Hospital of Berlin, Berlin, Germany.
Br J Dermatol. 2007 May;156 Suppl 3:25-33. doi: 10.1111/j.1365-2133.2007.07856.x.
In addition to having anti-inflammatory activities, nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit neoplastic cell proliferation by inducing apoptosis. Diclofenac is the anti-neoplastic compound in diclofenac 3% gel (Solaraze) used for topical treatment of actinic keratosis (AK). Main target of NSAIDs seems to be the inhibition of cyclo-oxygenase-2 (COX-2), which is overexpressed in several epithelial tumours and catalyses the synthesis of prostaglandins. The precise mechanism of action of diclofenac in cutaneous cells is still unclear, but induction of apoptosis is a key effect of anti-neoplastic drugs, including NSAIDs. In this paper we give an overview of the anti-tumoural activities of NSAIDs with emphasis on induction of apoptosis. Cyclo-oxygenase-2-mediated synthesis of prostaglandin E(2) (PGE(2)) leads to activation of mitogen-activated protein kinase (MAPK), as well as phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Induction of the anti-apoptotic Bcl-2 and Mcl-1, as well as activation of the caspase-8 inhibitor cFLIP have been reported. In addition, altered lipid concentrations in the cytoplasmic membrane may modulate death receptor activities. Downregulation of both the intrinsic mitochondrial and the extrinsic pathways have been reported. Our data demonstrate induced apoptosis and activation of the caspase cascade in three of four cutaneous squamous cell carcinoma (SCC) cell lines, after treatment with diclofenac plus hyaluronic acid and diclofenac alone; one cell line remained nonresponsive. The effects were less pronounced in normal keratinocytes and cytotoxic effects were not seen. Detailed analysis of apoptosis pathways employed by diclofenac in these cells may help to improve therapeutic strategies and to overcome possible mechanisms that are involved in nonresponsiveness.
除了具有抗炎活性外，非甾体抗炎药（NSAIDs）还通过诱导细胞凋亡来抑制肿瘤细胞增殖。双氯芬酸是3%双氯芬酸凝胶（Solaraze）中的抗肿瘤化合物，用于光化性角化病（AK）的局部治疗。NSAIDs的主要靶点似乎是抑制环氧合酶-2（COX-2），其在几种上皮肿瘤中过度表达并催化前列腺素的合成。双氯芬酸在皮肤细胞中的精确作用机制仍不清楚，但诱导细胞凋亡是包括NSAIDs在内的抗肿瘤药物的关键作用。在本文中，我们概述了NSAIDs的抗肿瘤活性，重点是细胞凋亡的诱导。环氧合酶-2介导的前列腺素E2（PGE2）合成导致丝裂原活化蛋白激酶（MAPK）以及磷脂酰肌醇3激酶（PI3K）/Akt途径的激活。据报道，抗凋亡的Bcl-2和Mcl-1被诱导，以及半胱天冬酶-8抑制剂cFLIP被激活。此外，细胞质膜中脂质浓度的改变可能调节死亡受体活性。据报道，内在线粒体途径和外在途径均下调。我们的数据表明，在用双氯芬酸加透明质酸和单独使用双氯芬酸处理后，四种皮肤鳞状细胞癌（SCC）细胞系中的三种出现了诱导的细胞凋亡和半胱天冬酶级联反应的激活；一种细胞系无反应。在正常角质形成细胞中，这些作用不太明显，且未观察到细胞毒性作用。对双氯芬酸在这些细胞中采用的细胞凋亡途径进行详细分析，可能有助于改进治疗策略，并克服与无反应性相关的可能机制。
