Balakin Konstantin V, Ivanenkov Yan A, Tkachenko Sergey E, Kiselyov Alex S, Ivachtchenko Alexandre V
ChemDiv, Inc., San Diego, CA 92121, USA.
Curr Cancer Drug Targets. 2008 Jun;8(4):299-340. doi: 10.2174/156800908784533490.
Chemokines are a family of small proteins inducing directed cell migration via specific chemokine receptors, which play important roles in a variety of biological and pathological processes. Their respective ligands act as proinflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors, and also have a role in pathological conditions that require neovascularization. Therapeutic strategies based on modulation of chemokine receptor pathways were reported to be promising clinical strategies in the treatment of inflammatory diseases and viral infections. Recent studies have been also demonstrated that chemokines and chemokine receptors are produced by many different cell types, including tumor cells. Overexpression of many chemokine and chemokine receptors in tumor cells suggests that they are crucial regulators of the levels of tumor infiltrating leukocytes implicated in the tumorigenesis of multiple human cancers. In the tumor microenvironment they control a variety of biological activities, such as production and deposition of collagen, activation of matrix-digesting enzymes, stimulation of cell growth, inhibition of apoptosis and promotion of neo-angiogenesis and metastasis. In this review we elucidate key aspects of chemokine signaling as well as clinically relevant strategies to modulation of chemokine receptor activity in the treatment of cancer with emphasis on small-molecule agents. We also elucidate various research strategies which were found to be useful in the design of chemokine receptor targeted therapeutics.
趋化因子是一类小蛋白，通过特定的趋化因子受体诱导细胞定向迁移，在多种生物和病理过程中发挥重要作用。它们各自的配体作为促炎介质，主要控制白细胞向特定组织的迁移以及黏附受体的上调，并且在需要新血管形成的病理状况中也发挥作用。据报道，基于调节趋化因子受体途径的治疗策略是治疗炎症性疾病和病毒感染的有前景的临床策略。最近的研究还表明，趋化因子和趋化因子受体由包括肿瘤细胞在内的许多不同细胞类型产生。肿瘤细胞中许多趋化因子和趋化因子受体的过表达表明它们是涉及多种人类癌症肿瘤发生的肿瘤浸润白细胞水平的关键调节因子。在肿瘤微环境中，它们控制多种生物学活性，如胶原蛋白的产生和沉积、基质消化酶的激活、细胞生长的刺激、细胞凋亡的抑制以及新血管生成和转移的促进。在本综述中，我们阐明趋化因子信号传导的关键方面以及在癌症治疗中调节趋化因子受体活性的临床相关策略，重点是小分子药物。我们还阐明了在设计趋化因子受体靶向治疗药物中发现有用的各种研究策略。
