Therapeutic Senolysis of Axitinib-Induced Senescent Human Lung Cancer Cells

• Published in: Cancers Vol. 16; no. 16; p. 2782
• Main Authors: Kotani, Hitoshi, Han, Wei, Iida, Yuichi, Tanino, Ryosuke, Katakawa, Kazuaki, Okimoto, Tamio, Tsubata, Yukari, Isobe, Takeshi, Harada, Mamoru
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 07.08.2024; MDPI
• Subjects: Adenocarcinoma; AKT protein; Analysis; Apoptosis; Axitinib; Bcl-x protein; Breast cancer; Cancer cells; Cancer therapies; Caspase; Cell cycle; Cell death; Cell growth; Cell size; Endothelial cells; Extracellular signal-regulated kinase; Flow cytometry; Gene expression; Growth factor receptors; Health aspects; Kinases; Life sciences; Lung cancer; Mesothelioma; Monoclonal antibodies; Mutation; Pemetrexed; Phosphorylation; Reactive oxygen species; RNA; Senescence; senolysis; Tumor cell lines; Tumors; Tyrosine; Tyrosine kinase inhibitors; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Xenografts; β-Galactosidase; Japan; United States > US; lung cancer; senescence; senolysis; axitinib
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16162782

Tyrosine kinase inhibitors (TKIs) inhibit receptor-mediated signals in cells. Axitinib is a TKI with high specificity for vascular endothelial growth factor receptors (VEGFRs). We determined whether axitinib could induce senescence in human cancer cells and be lysed by the senolytic drug ABT-263. Human lung and breast adenocarcinoma cell lines were used. These cells were cultured with axitinib or a multi-target TKI lenvatinib. The expression of β-galactosidase, VEGFRs, Ki-67, reactive oxygen species (ROS) of cancer cells, and their BrdU uptake were evaluated by flow cytometry. The mRNA expression of p21 and IL-8 was examined by quantitative PCR. The effects of TKIs on phosphorylation of Akt and Erk1/2, as downstream molecules of VEGFR signaling, were examined by immunoblot. The in vivo anti-cancer effect was examined using a xenograft mice model. Axitinib, but not lenvatinib, induced cellular senescence (increased cell size and enhanced expression of β-galactosidase) in all adenocarcinoma cell lines. Axitinib-induced senescence was unrelated to the expression of VEGFRs on cancer cells. ROS were involved in axitinib-induced senescence. Axitinib-induced senescent lung adenocarcinoma A549 cells were drastically lysed by ABT-263. In A549-xenografted mice, combination therapy with axitinib and ABT-263 significantly suppressed tumor growth with the induction of apoptotic cancer cells.