ArticleCurrent cancer drug targets2010
Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy.
Article in Current cancer drug targets, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- Biodegradable Nanoparticles Encapsulating Murine Double Minute 2 siRNA to Treat Peritoneal Dissemination of Colon Cancer.International journal of molecular sciences · 2025Article
- Gemcitabine resistance by CITED4 upregulation via the regulation of BIRC2 expression in pancreatic cancer.Journal of biomedical science · 2025Article
- Personalized Medicine in Pancreatic Cancer: The Promise of Biomarkers and Molecular Targeting with Dr. Michael J. Pishvaian.Cancers · 2024Review
- MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.Pharmacological reviews · 2024Review
- The circadian clock as a potential biomarker and therapeutic target in pancreatic cancer.Molecular and cellular biochemistry · 2024Review
- Review
- An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression.Cancer metastasis reviews · 2021Review
- Model-based optimization of combination protocols for irradiation-insensitive cancers.Scientific reports · 2020Article
- Circadian Genes as Therapeutic Targets in Pancreatic Cancer.Frontiers in endocrinology · 2020Review
- Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine.Gut · 2019Review
- Review
- Surface Plasmon Resonance Sensing of Biorecognition Interactions within the Tumor Suppressor p53 Network.Sensors (Basel, Switzerland) · 2017Review
- Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes.International journal of molecular sciences · 2017Review
- Dual targeting of MDM2 with a novel small-molecule inhibitor overcomes TRAIL resistance in cancer.Carcinogenesis · 2016Article
- Carnosic acid slows photoreceptor degeneration in the Pde6b(rd10) mouse model of retinitis pigmentosa.Scientific reports · 2016Article
- Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy.Expert opinion on therapeutic targets · 2016Review
- Longitudinal tracking of single live cancer cells to understand cell cycle effects of the nuclear export inhibitor, selinexor.Scientific reports · 2015Article
- An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells.Virology · 2015Article
- Gene therapy in pancreatic cancer.World journal of gastroenterology · 2014Review
- 7B7: a novel antibody directed against the Ku70/Ku80 heterodimer blocks invasion in pancreatic and lung cancer cells.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2014Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The present study is the first to show in pancreatic cancer (PC) the growth inhibition and apoptosis by novel MDM2 inhibitors (MI-319 & 219) through reactivation of p53 pathway. Our results highlight two new secondary targets of MDM2 inhibitor 'SIRT1' and Ku70. SIRT1 which has a role in ageing and cancer and is known to regulate p53 signaling through acetylation. Ku70 is a key component of non-homologous end joining machinery in the DNA damage pathway and is known to regulate apoptosis by blocking Bax entry into mitochondria. Growth inhibition and apoptosis by MI-219, MI-319 was accompanied by increase in levels of p53 along with p21(WAF1) and the proapoptotic Puma. SiRNA against p21(WAF1) abrogated the growth inhibition of PC cells confirming p21(WAF1) as a key player downstream of activated p53. Immunoprecipitation-western blot analysis revealed reduced association of MDM2-p53 interaction in drug exposed PC cells. In combination studies, the inhibitors synergistically augmented anti-tumor effects of therapeutic drug gemcitabine both in terms of cell growth inhibition as well as apoptosis. Surface plasmon resonance studies confirmed strong binding between MI-319 and Ku70 (K(D) 170 nM). Western blot revealed suppression of SIRT1 and Ku70 with simultaneous upregulation of acetyl-p53 (Lys379) and Bax. Co-Immunoprecipitation studies confirmed that MI-319 could disrupt Ku70-Bax and SIRT1-Bax interaction. Further, using wt-p53 xenograft of Capan-2, we found that oral administration of MI-319 at 300 mg/kg for 14 days resulted in significant tumor growth inhibition without any observed toxicity to the animals. No tumor inhibition was found in mut-p53 BxPC-3 xenografts. In light of our results, the inhibitors of MDM2 warrant clinical investigation as new agents for PC treatment.
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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.