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

// Daria Marley Kemp 1 , Alyson Pidich 1 , Mary Larijani 1 , Rebecca Jonas 1 , Elizabeth Lash 1 , Takami Sato 2 , Mizue Terai 2 , Maria De Pizzol 3 , Marcello Allegretti 3 , Olga Igoucheva 1 and Vitali Alexeev 1 1 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA 2 Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA 3 Dompe Farmaceutici SpA, Via Campo di Pile, L’Aquila, Italy Correspondence to: Vitali Alexeev, email: // Keywords : CXCR1/2 inhibitor, melanoma, tumor growth inhibition, melanoma apoptosis, tumor microenvironment Received : January 04, 2017 Accepted : January 11, 2017 Published : January 24, 2017 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.