title: 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.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Daria Marley
authors.initials: DM
authors.lastname: Kemp
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Alyson
authors.initials: A
authors.lastname: Pidich
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Larijani
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jonas
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lash
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Takami
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Mizue
authors.initials: M
authors.lastname: Terai
authors.affiliation: Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: De Pizzol
authors.affiliation: Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Allegretti
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Igoucheva
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Vitali
authors.initials: V
authors.lastname: Alexeev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C511776:2'-((4'-trifluoromethanesulfonyloxy)phenyl)-N-methanesulfonylpropionamide; D000970:Antineoplastic Agents; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides
keywords: CXCR1/2 inhibitor; melanoma; melanoma apoptosis; tumor growth inhibition; tumor microenvironment