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Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment.

ABSTRACT: 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.

SUBMITTER: Kemp DM

PROVIDER: S-EPMC5362416 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment.

Kemp Daria Marley DM Pidich Alyson A Larijani Mary M Jonas Rebecca R Lash Elizabeth E Sato Takami T Terai Mizue M De Pizzol Maria M Allegretti Marcello M Igoucheva Olga O Alexeev Vitali V

Oncotarget 20170201 9

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 ...[more]

PMID: 28129639

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Project description:Glioma is the most common malignant brain tumor. Previous studies have reported that calnexin (CANX) is significantly up-regulated in a variety of malignant tumors, including glioma, but its biological function and mechanism in glioma is still unclear. In this study, differentially expressed proteins in 3 primary glioblastoma multiforme (GBM) tissues and 3 paracancer tissues were identified by liquid chromatography-tandem mass spectrometry-based proteomic and bioinformatic analysis. The biological function and molecular mechanism of CANX were studied in glioma cell lines (T98G and A172) by CCK-8 assay, matrigel invasion assay, wound healing assay, flow cytometry and so on. Bioinformatics methods were used to analyze the immune microenvironment of glioma patients in TCGA database, and single cell sequencing data of 8 cases of untreated primary GBM in GEO database were analyzed. Proteomic analysis found that CANX was significantly overexpressed in glioma tissues comparing with paracancer tissues. The data from TCGA validated this result and showed that CANX was associated with poor prognosis of patients. A series of experiments at the cellular level found that CANX overexpression significantly enhanced the proliferation, migration and invasion ability of GBM cells, whereas CANX silencing had opposite effects. Further research found this effect may be mediated through the activation of the PI3K/AKT/mTOR signaling. In addition, immune infiltration analysis found that CANX high-expression glioma tissues exhibited fewer CD8+ T cells, natural killer cells and mast cells, along with significantly decreased tumor purity and significantly increased immune checkpoints expression. Single cell sequencing data analysis indicated that CANX was primarily expressed in astrocytes and dendritic cells. In conclusion, this study suggested that CANX may promote the malignant progression of glioma through PI3K/AKT/mTOR signaling pathway and play an important role in glioma immune escape. Therefore, CANX may be a valuable therapeutic target for glioma.

Dataset Information

Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment.

Publications

Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment.

Similar Datasets

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