Antitumor Activity of Axitinib in Lung Carcinoids: A Preclinical Study

Author:

Dicitore Alessandra1ORCID,Gaudenzi Germano2,Carra Silvia3,Cantone Maria Celeste2,Oldani Monica2,Saronni Davide1,Borghi Maria Orietta45ORCID,Grotteschi Jacopo1,Persani Luca13ORCID,Vitale Giovanni12ORCID

Affiliation:

1. Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy

2. Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy

3. Laboratory of Endocrine and Metabolic Research, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy

4. Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy

5. Experimental Laboratory of Immuno-Rheumatology, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy

Abstract

Lung carcinoids (LCs) comprise well-differentiated neuroendocrine tumors classified as typical (TCs) and atypical (ACs) carcinoids. Unfortunately, curative therapies remain elusive for metastatic LCs, which account for 25–30% of cases. This study evaluated the antitumor activity of axitinib (AXI), a second-generation tyrosine kinase inhibitor selectively targeting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3) in human lung TC (NCI-H727, UMC-11, NCI-H835) and AC (NCI-H720) cell lines. In vitro and in vivo (zebrafish) assays were performed following AXI treatment to gather several read-outs about cell viability, cell cycle, the secretion of proangiogenic factors, apoptosis, tumor-induced angiogenesis and migration. AXI demonstrated relevant antitumor activity in human LC cells, with pronounced effects observed in UMC-11 and NCI-H720, characterized by cell cycle perturbation and apoptosis induction. AXI significantly hindered tumor induced-angiogenesis in Tg(fli1a:EGFP)y1 zebrafish embryos implanted with all LC cell lines and also reduced the invasiveness of NCI-H720 cells, as well as the secretion of several proangiogenic factors. In conclusion, our study provides initial evidence supporting the potential anti-tumor activity of AXI in LC, offering a promising basis for future investigations in mammalian animal models and, eventually, progressing to clinical trials.

Funder

Neuroendocrine Tumor Research Foundation

Italian Ministry of Health

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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