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Antitumor Activity of Axitinib in Lung Carcinoids: A Preclinical Study
Alessandra Dicitore1, Germano Gaudenzi2, Silvia Carra3
1Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 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) 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.
Insights
Axitinib (AXI) shows antitumor potential against lung carcinoids (LCs). This tyrosine kinase inhibitor reduced cell viability, induced apoptosis, and inhibited angiogenesis in preclinical models, suggesting AXI as a promising therapy for metastatic LCs.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Lung carcinoids (LCs) are neuroendocrine tumors with limited curative options for metastatic disease.
- Metastatic LCs account for 25-30% of cases, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To evaluate the antitumor activity of axitinib (AXI), a VEGFR inhibitor, in human typical and atypical lung carcinoid cell lines.
- To assess AXI's effects on cell viability, cell cycle, apoptosis, angiogenesis, and migration in vitro and in vivo.
Main Methods:
- In vitro assays using human lung carcinoid cell lines (NCI-H727, UMC-11, NCI-H835, NCI-H720).
- In vivo studies in zebrafish embryos (Tg(fli1a:EGFP)) to assess tumor-induced angiogenesis and cell invasiveness.
- Analysis of cell viability, cell cycle progression, apoptosis, proangiogenic factor secretion, and tumor cell migration.
Main Results:
- Axitinib demonstrated significant antitumor activity in lung carcinoid cells, particularly UMC-11 and NCI-H720.
- AXI induced cell cycle perturbation and apoptosis in treated lung carcinoid cells.
- AXI significantly inhibited tumor-induced angiogenesis in zebrafish models and reduced invasiveness and proangiogenic factor secretion.
Conclusions:
- Axitinib exhibits promising preclinical antitumor activity against lung carcinoids.
- These findings support further investigation of AXI in mammalian models and potential clinical trials for metastatic LCs.
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