Denoyer Delphine, Masaldan Shashank, La Fontaine Sharon, Cater Michael A
Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria, Australia.
Metallomics. 2015 Nov;7(11):1459-76. doi: 10.1039/c5mt00149h. Epub 2015 Aug 27.
Copper is an essential micronutrient involved in fundamental life processes that are conserved throughout all forms of life. The ability of copper to catalyze oxidation-reduction (redox) reactions, which can inadvertently lead to the production of reactive oxygen species (ROS), necessitates the tight homeostatic regulation of copper within the body. Many cancer types exhibit increased intratumoral copper and/or altered systemic copper distribution. The realization that copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes. Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels. The therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties. Also under investigation is the use of copper to replace platinum in coordination complexes currently used as mainstream chemotherapies. In comparison to platinum-based drugs, these promising copper coordination complexes may be more potent anticancer agents, with reduced toxicity toward normal cells and they may potentially circumvent the chemoresistance associated with recurrent platinum treatment. In addition, cancerous cells can adapt their copper homeostatic mechanisms to acquire resistance to conventional platinum-based drugs and certain copper coordination complexes can re-sensitize cancer cells to these drugs. This review will outline the biological importance of copper and copper homeostasis in mammalian cells, followed by a discussion of our current understanding of copper dysregulation in cancer, and the recent therapeutic advances using copper coordination complexes as anticancer agents.
铜是一种必需的微量营养素，参与所有生命形式中都保守的基本生命过程。铜催化氧化还原反应的能力可能会无意中导致活性氧（ROS）的产生，这就需要对体内铜进行严格的稳态调节。许多癌症类型表现出肿瘤内铜含量增加和/或全身铜分布改变。认识到铜是肿瘤进展多个方面（包括生长、血管生成和转移）的限制因素，促使人们开发铜特异性螯合剂作为抑制这些过程的疗法。另一种治疗方法是利用特定的离子载体将铜输送到细胞中，以提高细胞内铜水平。当细胞内铜被强制增加时，正常细胞和癌细胞之间的治疗窗口是开发具有抗癌特性的铜离子载体的前提。目前也在研究使用铜来替代当前用作主流化疗药物的配位络合物中的铂。与铂类药物相比，这些有前景的铜配位络合物可能是更有效的抗癌剂，对正常细胞的毒性降低，并且它们可能潜在地规避与铂类药物反复治疗相关的化学耐药性。此外，癌细胞可以调整其铜稳态机制以获得对传统铂类药物的抗性，而某些铜配位络合物可以使癌细胞对这些药物重新敏感。本综述将概述铜和铜稳态在哺乳动物细胞中的生物学重要性，随后讨论我们目前对癌症中铜失调的理解，以及使用铜配位络合物作为抗癌剂的最新治疗进展。
