Therapeutic Senolysis of Axitinib-Induced Senescent Human Lung Cancer Cells

Author:

Kotani Hitoshi1,Han Wei1,Iida Yuichi1ORCID,Tanino Ryosuke2ORCID,Katakawa Kazuaki3ORCID,Okimoto Tamio2,Tsubata Yukari2ORCID,Isobe Takeshi2,Harada Mamoru1

Affiliation:

1. Department of Immunology, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan

2. Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan

3. Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, Yokohama 244-0806, Kanagawa, Japan

Abstract

Background: Tyrosine kinase inhibitors (TKIs) inhibit receptor-mediated signals in cells. Axitinib is a TKI with high specificity for vascular endothelial growth factor receptors (VEGFRs). Aim: We determined whether axitinib could induce senescence in human cancer cells and be lysed by the senolytic drug ABT-263. Methods: 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. Results: 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.

Funder

JSPS KAKENHI

Publisher

MDPI AG

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