Smaldone Gerardina, Di Matteo Francesca, Castelluccio Roberta, Napolitano Valeria, Miranda Maria Rosaria, Manfra Michele, Campiglia Pietro, Vestuto Vincenzo
Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy.
PhD Program in Drug Discovery and Development, University of Salerno, 84084 Fisciano, Italy.
Molecules. 2025 Mar 20;30(6):1380. doi: 10.3390/molecules30061380.
Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents.
癌症是导致过早死亡的主要原因之一，它源于遗传和表观遗传突变，这些突变将正常细胞转化为肿瘤细胞，使其能够增殖、逃避细胞死亡并刺激血管生成。最近的证据表明，趋化因子在肿瘤发展过程中至关重要，它能激活促进增殖、侵袭和转移的受体。CXCR4/CXCL12信号通路作为一种有前景的癌症治疗靶点正受到关注。CXCR4是一种趋化因子受体，在包括肾、肺、脑、前列腺、乳腺、胰腺、卵巢癌以及黑色素瘤等多种类型的癌症中常常过度表达。当它与其内源性配体CXCL12结合时，会促进细胞存活、增殖和迁移，这些是造血干细胞在骨髓中留存以及淋巴细胞移动的关键机制。CXCR4在癌症中的广泛表达，加上CXCL12在各个器官中的持续存在，促使该轴的激活，进而促进血管生成、肿瘤进展和转移。鉴于CXCR4/CXCL12轴的有害作用，寻找选择性作用于该蛋白的药物是一项尚未解决的挑战。本综述旨在总结CXCR4拮抗剂作为潜在抗癌药物在设计和开发方面的最新进展。
