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SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Therapeutic Senolysis of Axitinib-Induced Senescent Human Lung Cancer Cells
Hitoshi Kotani1, Wei Han1, Yuichi Iida1
1Department of Immunology, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan.
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.
Insights
Axitinib, a tyrosine kinase inhibitor, induces cancer cell senescence and is effectively targeted by the senolytic drug ABT-263. Combination therapy significantly suppressed tumor growth in mice.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Tyrosine kinase inhibitors (TKIs) modulate cell signaling pathways.
- Axitinib specifically targets vascular endothelial growth factor receptors (VEGFRs).
Purpose of the Study:
- To investigate if axitinib induces senescence in human cancer cells.
- To determine if senescent cells induced by axitinib can be eliminated by the senolytic drug ABT-263.
Main Methods:
- Adenocarcinoma cell lines were treated with axitinib or lenvatinib.
- Senescence markers (β-galactosidase, cell size), VEGFR expression, Ki-67, reactive oxygen species (ROS), and proliferation (BrdU uptake) were analyzed.
- mRNA expression (p21, IL-8) and protein phosphorylation (Akt, Erk1/2) were assessed.
- In vivo efficacy was evaluated in a xenograft mouse model.
Main Results:
- Axitinib, unlike lenvatinib, induced cellular senescence in adenocarcinoma cell lines.
- Axitinib-induced senescence was independent of VEGFR expression and involved ROS.
- ABT-263 effectively lysed axitinib-induced senescent lung cancer cells.
- Combined axitinib and ABT-263 therapy suppressed tumor growth and increased apoptosis in vivo.
Conclusions:
- Axitinib is a potent inducer of cancer cell senescence.
- Senescent cancer cells induced by axitinib are susceptible to senolytic therapy with ABT-263.
- Combination therapy shows promise for cancer treatment by targeting both tumor growth and senescent cells.
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