Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via S. Pansini 5, 80131 Napoli, Italy.
Biochimie. 2013 Apr;95(4):934-45. doi: 10.1016/j.biochi.2012.12.012. Epub 2012 Dec 26.
Melanoma is an aggressive cutaneous cancer, whose incidence is growing in recent years, especially in the younger population. The favorable therapy for this neoplasm consists in its early surgical excision; otherwise, in case of late diagnosis, melanoma becomes very refractory to any conventional therapy. Nevertheless, the acute inflammatory response occurring after excision of the primary melanoma can affect the activation and/or regulation of melanoma invasion and metastasis. Nonsteroidal anti-inflammatory drugs (NSAIDs), widely employed in clinical therapy as cyclooxygenase inhibitors, also display a cytotoxic effect on some cancer cell lines; therefore, their possible usage in combination with conventional chemo- and radio-therapies of tumors is being considered. In particular, diclofenac, one of the most common NSAIDs, displays its anti-proliferative effect in many tumor lines, through an alteration of the cellular redox state. In this study, the possible anti-neoplastic potential of diclofenac on the human melanoma cell lines A2058 and SAN was investigated, and a comparison was made with the results obtained from the nonmalignant fibroblast cell line BJ-5ta. Either in A2058 or SAN, the diclofenac treatment caused typical apoptotic morphological changes, as well as an increase of the number of sub-diploid nuclei; conversely, the same treatment on BJ-5ta had only a marginal effect. The observed decrease of Bcl-2/Bax ratio and a parallel increase of caspase-3 activity confirmed the pro-apoptotic role exerted by diclofenac in melanoma cells; furthermore, the drug provoked an increase of the ROS levels, a decrease of mitochondrial superoxide dismutase (SOD2), the cytosolic translocation of both SOD2 and cytochrome c, and an increase of caspase-9 activity. Finally, the cytotoxic effect of diclofenac was amplified, in melanoma cells, by the silencing of SOD2. These data improve the knowledge on the effects of diclofenac and suggest that new anti-neoplastic treatments should be based on the central role of mitochondrion in cancer development; under this concern, the possible involvement of SOD2 as a novel target could be considered.
黑色素瘤是一种侵袭性皮肤癌，近年来其发病率呈上升趋势，尤其是在年轻人群中。这种肿瘤的有利治疗方法是早期手术切除；否则，一旦诊断延迟，黑色素瘤对任何常规治疗都变得非常耐药。然而，原发性黑色素瘤切除后发生的急性炎症反应会影响黑色素瘤侵袭和转移的激活和/或调节。非甾体抗炎药（NSAIDs）作为环氧化酶抑制剂在临床治疗中广泛应用，对一些癌细胞系也具有细胞毒性作用；因此，正在考虑将其与肿瘤的常规化疗和放疗联合使用。特别是，作为最常见的 NSAIDs 之一的双氯芬酸，通过改变细胞氧化还原状态，在许多肿瘤系中显示出其抗增殖作用。在这项研究中，研究了双氯芬酸对人黑色素瘤细胞系 A2058 和 SAN 的潜在抗肿瘤作用，并与非恶性成纤维细胞系 BJ-5ta 的结果进行了比较。在 A2058 或 SAN 中，双氯芬酸处理均导致典型的凋亡形态变化，以及亚二倍体核数量的增加；相反，相同的处理对 BJ-5ta 只有轻微的影响。观察到 Bcl-2/Bax 比值下降和 caspase-3 活性平行增加，证实了双氯芬酸在黑色素瘤细胞中发挥的促凋亡作用；此外，该药物还引起 ROS 水平升高、线粒体超氧化物歧化酶（SOD2）减少、SOD2 和细胞色素 c 从细胞质易位以及 caspase-9 活性增加。最后，在黑色素瘤细胞中，SOD2 的沉默增强了双氯芬酸的细胞毒性作用。这些数据提高了对双氯芬酸作用的认识，并表明新的抗肿瘤治疗方法应基于线粒体在癌症发展中的核心作用；在这方面，可以考虑 SOD2 作为新的靶标可能的参与。
