ArticleOncotarget2015
Axitinib induces DNA damage response leading to senescence, mitotic catastrophe, and increased NK cell recognition in human renal carcinoma cells.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 69 citations in OpenAlex.
- Metronomic cyclophosphamide attenuates mTOR-mediated expansion of regulatory T cells, but does not impact clinical outcome in patients with metastatic renal cell cancer treated with everolimus.Cancer immunology, immunotherapy : CII · 2019Trial
- Discovery of a novel VEGFR2 inhibitor using integrated structure-based docking study and functional validation: potential applications in targeted cancer therapy.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Article
- Multi-tyrosine kinase inhibitors: exploring immunomodulatory effects on various immune cell types in cancer.Cancer cell international · 2026Review
- KDM6A deficiency promotes tumor progression and resistance to cabozantinib treatment in clear cell renal cell carcinoma.Scientific reports · 2025Article
- Repurposing the Tyrosine Kinase Inhibitors Targeting FGFR and VEGFR Pathways for Cancer Therapy: A Comprehensive Review.Cancers · 2025Review
- Kinase-Targeted Therapies for Glioblastoma.International journal of molecular sciences · 2025Review
- Sesamin induces cell cycle arrest and upregulation of NKG2D ligands in MG‑63 cells and increases susceptibility to NK cell cytotoxicity.Experimental and therapeutic medicine · 2025Article
- NK cells in renal cell carcinoma and its implications for CAR-NK therapy.Frontiers in cell and developmental biology · 2025Review
- N-Acetyl-L-Cysteine (NAC) Blunts Axitinib-Related Adverse Effects in Preclinical Models of Glioblastoma.Cancer medicine · 2024Article
- Article
- Promoting reactive oxygen species accumulation to overcome tyrosine kinase inhibitor resistance in cancer.Cancer cell international · 2024Review
- Improving the power of drug toxicity measurements by quantitative nuclei imaging.Cell death discovery · 2024Article
- Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma.Cell death discovery · 2024Review
- Article
- Exploring the multifaceted antitumor activity of axitinib in lung carcinoids.Frontiers in endocrinology · 2024Article
- CombinationThyroid : official journal of the American Thyroid Association · 2023Article
- Targeting myeloid-derived suppressor cells to enhance natural killer cell-based immunotherapy.Pharmacology & therapeutics · 2022Review
- Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma.Frontiers in immunology · 2022Article
- A Profile of Avelumab Plus Axitinib in the Treatment of Renal Cell Carcinoma.Therapeutics and clinical risk management · 2022Review
- Integrated transcriptional-phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients.Clinical and translational medicine · 2021Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tyrosine kinase inhibitors (TKIs) including axitinib have been introduced in the treatment of renal cell carcinoma (RCC) because of their anti-angiogenic properties. However, no evidence are presently available on a direct cytotoxic anti-tumor activity of axitinib in RCC.Herein we reported by western blot analysis that axitinib treatment induces a DNA damage response (DDR) initially characterized by γ-H2AX phosphorylation and Chk1 kinase activation and at later time points by p21 overexpression in A-498 and Caki-2 RCC cells although with a different potency. Analysis by immunocytochemistry for the presence of 8-oxo-7,8-dihydro-2'-deoxyguanosine in cellular DNA and flow cytometry using the redox-sensitive fluorescent dye DCFDA, demonstrated that DDR response is accompanied by the presence of oxidative DNA damage and reactive oxygen species (ROS) generation. This response leads to G2/M cell cycle arrest and induces a senescent-like phenotype accompanied by enlargement of cells and increased senescence-associated β-galactosidase activity, which are abrogated by N-acetyl cysteine (NAC) pre-treatment. In addition, axitinib-treated cells undergo to cell death through mitotic catastrophe characterized by micronucleation and abnormal microtubule assembly as assessed by fluorescence microscopy.On the other hand, axitinib, through the DDR induction, is also able to increase the surface NKG2D ligand expression. Accordingly, drug treatment promotes NK cell recognition and degranulation in A-498 RCC cells in a ROS-dependent manner.Collectively, our results indicate that both cytotoxic and immunomodulatory effects on RCC cells can contribute to axitinib anti-tumor activity.
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