Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California 90089-9094, USA.
Anticancer Agents Med Chem. 2010 Jul;10(6):450-61. doi: 10.2174/1871520611009060450.
Cyclooxygenase 2 (COX-2) is frequently found up-regulated during pathological conditions and in cancer, where it is thought to support carcinogenesis and tumor angiogenesis. The development of newer-generation non-steroidal anti-inflammatory drugs (NSAIDs) able to more selectively inhibit cyclooxygenase 2 (COX-2) raised expectations that these agents might be beneficial for cancer prevention and therapy. However, while chemopreventive effects of some selective COX-2 inhibitors have been established, it has remained unpersuasive whether these new NSAIDs, such as celecoxib, rofecoxib or etoricoxib, are able to exert cancer therapeutic effects, i.e., whether they would be beneficial for the treatment of advanced cancers that are already grown and established. This issue was further complicated by findings that celecoxib was able to exert pronounced pro-apoptotic effects in vitro and in vivo in the absence of any apparent involvement of COX-2. In fact, newly synthesized close structural analogs of the celecoxib molecule revealed that it was possible to separate COX-2 inhibitory function from the ability to trigger apoptosis; for example, the analog 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet exerts increased cytotoxic potency. This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib.
环氧化酶 2（COX-2）在病理条件下和癌症中经常被发现上调，在癌症中，它被认为支持癌发生和肿瘤血管生成。新一代非甾体抗炎药（NSAIDs）的开发能够更选择性地抑制环氧化酶 2（COX-2），这使得人们期望这些药物可能有益于癌症的预防和治疗。然而，虽然一些选择性 COX-2 抑制剂的化学预防作用已经得到确立，但仍然没有令人信服的证据表明这些新型 NSAIDs，如塞来昔布、罗非昔布或依托考昔，能够发挥癌症治疗作用，即它们是否有益于治疗已经生长和建立的晚期癌症。这个问题进一步复杂化，因为发现塞来昔布在没有明显涉及 COX-2 的情况下，能够在体外和体内发挥明显的促凋亡作用。事实上，塞来昔布分子的新合成的紧密结构类似物表明，有可能将 COX-2 抑制功能与触发凋亡的能力分开；例如，类似物 2,5-二甲基塞来昔布（DMC）已经失去了 COX-2 抑制功能，但发挥出增强的细胞毒性效力。这篇综述将总结 NSAIDs（特别是塞来昔布）在恶性神经胶质瘤的临床前和临床研究中的探索性治疗应用的相关结果。将提出几个 COX-2 独立的靶点，并将讨论 DMC 如何有助于阐明它们与塞来昔布推测的 COX-2 独立的杀肿瘤作用的相关性。
