ArticleMolecular carcinogenesis2013
Nutlin-3 enhances sorafenib efficacy in renal cell carcinoma.
Article in Molecular carcinogenesis, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 citations in OpenAlex.
- The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status.Haematologica · 2012Trial
- Molecular Drivers of Chromophobe Renal Cell Carcinoma Revealed Through Genomic Analysis Using AACR Project GENIE.Life (Basel, Switzerland) · 2025Article
- Review
- Anlotinib suppresses the DNA damage response by disrupting SETD1A and inducing p53-dependent apoptosis in Transformed Follicular Lymphoma.International journal of medical sciences · 2024Article
- Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer.Biomolecules · 2022Review
- Overexpression of MFN2 alleviates sorafenib-induced cardiomyocyte necroptosis via the MAM-CaMKIIδ pathwayTheranostics · 2022Article
- Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance.International journal of biological sciences · 2022Review
- Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists.Cancers · 2019Review
- Cell death-based treatment of neuroblastoma.Cell death & disease · 2018Review
- TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours.Molecular cancer · 2017Article
- Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas.PloS one · 2015Article
- Drugging the p53 pathway: understanding the route to clinical efficacy.Nature reviews. Drug discovery · 2014Review
- Targeting p53-MDM2-MDMX loop for cancer therapy.Sub-cellular biochemistry · 2014Review
- The MDM2-p53 pathway revisited.Journal of biomedical research · 2013Article
- A novel combination therapy approach for the treatment of acute myeloid leukemia: the multi-kinase inhibitor sorafenib and the HDM2 inhibitor nutlin-3.Haematologica · 2012Article
- The MDM2 small-molecule inhibitor RG7388 leads to potent tumor inhibition in p53 wild-type neuroblastoma.Cell death discoveryArticle
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 1 country.
Funding
Abstract
The renal cell carcinoma (RCC) is one of the top 10 cancers in USA. The renal tumors are highly angiogenic and are resistant to conventional interventions, particularly radiotherapy. The advent of multi-specific tyrosine kinase inhibitor sorafenib has improved the progression-free survival in RCC, but overall survival in recurrent and metastatic RCC is still a concern that has lead to characterization of combinatorial regimens. Hence, we studied the effect of combination of nutlin-3, an MDM2 inhibitor, which increases p53 levels, and sorafenib in RCC. Sorafenib along with nutlin-3 synergistically inhibited the cell survival and enhanced caspase-3 cleavage leading to apoptosis in RCC. Nutlin-3 and sorafenib were more effective in reducing the migration of RCC, in combination than as single agents. Sorafenib and nutlin-3 decreased the phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) and ERK along with inducing p53 activity. The sorafenib and nutlin-3 co-treatment lead to enhanced levels of p53, p-p53, and increase in the levels of p53 pro-apoptotic effector PUMA, Bax, and decrease in the anti-apoptotic Bcl-2 levels. Importantly, our studies revealed that sorafenib alone can activate p53 in a concentration dependent manner. Thus, co-treatment of nutlin-3 with sorafenib leads to increased half-life of p53, which in turn can be activated by sorafenib, to induce downstream pro-apoptotic and anti-proliferative effects. This is the first report showing the synergistic effect of sorafenib and nutlin-3 while providing a strong clinical-translational rationale for further testing of sorafenib and nutlin-3 combinatorial regimen in human RCC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.