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Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by
Daria Marley Kemp1, Alyson Pidich1, Mary Larijani1
1Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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.
Insights
Ladarixin (LDX), a dual CXCR1/2 inhibitor, effectively reduced melanoma progression by inhibiting cell motility and inducing apoptosis. LDX also demonstrated anti-angiogenic and anti-tumorigenic effects in preclinical models.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- CXCR1 and CXCR2 chemokine receptors and their ligands are implicated in tumor progression.
- Previous CXCR1/2 inhibitors faced challenges due to signal redundancy and toxicity.
Purpose of the Study:
- To investigate the efficacy of Ladarixin (LDX), a novel small molecule dual CXCR1/2 inhibitor, against experimental human melanomas.
- To elucidate the mechanisms underlying LDX's effects on melanoma progression.
Main Methods:
- In vitro and in vivo studies using melanoma cell lines and xenografts.
- Assessment of cell motility, apoptosis, signaling pathways (AKT, NF-kB), macrophage polarization, angiogenesis, and tumor self-renewal.
- Systemic administration of LDX in melanoma-bearing mice.
Main Results:
- LDX inhibited melanoma cell motility and induced apoptosis in vitro and in vivo.
- LDX suppressed AKT and NF-kB signaling pathways.
- Systemic LDX treatment polarized intratumoral macrophages to M1 phenotype, reduced angiogenesis, and inhibited melanoma self-renewal.
Conclusions:
- Ladarixin demonstrates therapeutic potential for various melanoma types by inhibiting CXCR1/2.
- LDX exhibits multifactorial anti-melanoma effects, including direct anti-tumor activity and modulation of the tumor microenvironment.
- LDX offers a promising strategy for melanoma treatment, overcoming limitations of previous approaches.
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