Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment.
Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment.
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DOI：
10.18632/oncotarget.14803
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发表时间：
2017-02-28
期刊：
影响因子：
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通讯作者：
Alexeev V
中科院分区：
文献类型：
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作者：
Kemp DM;Pidich A;Larijani M;Jonas R;Lash E;Sato T;Terai M;De Pizzol M;Allegretti M;Igoucheva O;Alexeev V
CXCR 1和CXCR 2趋化因子受体及其配体（CXCL 1/2/3/7/8）在肿瘤进展中起重要作用。据报道，迄今为止测试的CXCR 1/2拮抗剂和趋化因子靶向抗体在体外和动物模型中影响恶性细胞。然而，多余的趋化信号和毒性阻碍了这些方法的进一步临床开发。在这项临床前研究中，我们研究了一种新型小分子双重CXCR 1/2抑制剂Ladarixin（LDX）减弱实验性人类黑色素瘤进展的能力。我们的数据表明，LDX介导的抑制CXCR 1/2废除运动和诱导细胞凋亡培养的皮肤和葡萄膜黑色素瘤细胞和异种移植物的分子缺陷与恶性表型无关。这些作用是通过抑制AKT和NF-kB信号通路介导的。此外，用LDX全身治疗荷黑色素瘤小鼠也使瘤内巨噬细胞极化为M1表型，消除瘤内新生血管生成并抑制黑色素瘤自我更新。总的来说，这些研究概述了成功抑制恶性细胞的CXCR 1/2的前期研究，并证明了Ladarixin对皮肤和葡萄膜黑色素瘤的多因素作用，表明LDX在治疗各种黑色素瘤类型中的治疗效用。
CXCR1 and CXCR2 chemokine receptors and their ligands (CXCL1/2/3/7/8) play an important role in tumor progression. Tested to date CXCR1/2 antagonists and chemokine-targeted antibodies were reported to affect malignant cells in vitro and in animal models. Yet, redundancy of chemotactic signals and toxicity hinder further clinical development of these approaches. In this pre-clinical study we investigated the capacity of a novel small molecule dual CXCR1/2 inhibitor, Ladarixin (LDX), to attenuate progression of experimental human melanomas. Our data showed that LDX-mediated inhibition of CXCR1/2 abrogated motility and induced apoptosis in cultured cutaneous and uveal melanoma cells and xenografts independently of the molecular defects associated with the malignant phenotype. These effects were mediated by the inhibition of AKT and NF-kB signaling pathways. Moreover, systemic treatment of melanoma-bearing mice with LDX also polarized intratumoral macrophages to M1 phenotype, abrogated intratumoral de novo angiogenesis and inhibited melanoma self-renewal. Collectively, these studies outlined the pre-requisites of the successful CXCR1/2 inhibition on malignant cells and demonstrated multifactorial effects of Ladarixin on cutaneous and uveal melanomas, suggesting therapeutic utility of LDX in treatment of various melanoma types.