MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function
Open accessAbstract
Small molecule inhibitors (SMIs) of murine double minute 2 (MDM2) are known to restore the apoptotic and cell cycle regulatory functions of p53 by disrupting the MDM2-p53 interaction. In principle, these SMIs are not effective against tumours with mutation in the tumour suppressor p53 (mut-p53), which is known to be present in approximately 50% of all cancers. In this study we are reporting, for the first time, that MI-319 in combination with cisplatin induced cell growth inhibition and apoptosis in pancreatic cancer (PC) cells irrespective of their p53 mutational status. MI-319-cisplatin combination synergistically suppressed cell growth (MTT Combination Index [CI]<1) and colony formation (clonogenic assay) and induced apoptosis. Western blot analysis and siRNA silencing studies in mutant as well as p53 null cells highlighted a mechanism involving p73 which is also known to be under the regulation of MDM2, and unlike p53, it is rarely mutated in PC. Down-regulating MDM2 using siRNA enhanced p73 reactivation and increased cell death. Further, the combination effectively reduced tumour growth in both wt-p53 and mut-p53 tumour xenograft models (50% Capan-2 animals were tumour free). Consistent with our in vitro results, remnant tumour tissue analysis showed up-regulation of p73 and the cell cycle regulator p21. In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin, and thus warrants further clinical investigation in human pancreatic tumours containing both wt-p53 and mut-p53.
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A cisplatin plus MI-319 combination was efficacious in human pancreatic ductal adenocarcinoma models in vitro and in vivo independently of p53 status.
“In addition, a cisplatin/MI-319 combination demonstrated efficacy in human PDAC models in vitro and in vivo independent of the p53 status.15”
From Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death (2013) · cites this paper as [15]
The Mdm2 inhibitors MI-319 and Nutlin 3a efficiently induce apoptosis in the human p53 wild-type pancreatic ductal adenocarcinoma cell line Capan-2 in vitro.
“The Mdm2 inhibitors MI-319 and Nutlin 3a efficiently induce apoptosis in the human p53 wild-type PDAC cell line Capan-2 in vitro 14,15”
From Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death (2013) · cites this paper as [15]
MI-319 suppressed growth of a Capan-2-based xenograft model in vivo.
“and MI-319 suppressed growth of a Capan-2-based xenotransplant model in vivo.15”
From Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death (2013) · cites this paper as [15]
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Self-citation
- Authors
- Azmi, A. S., Aboukameel, A., Banerjee, S., Wang, Z., Mohammad, M., Wu, J., Wang, S., Yang, D., Philip, P. A., Sarkar, F. H., & Mohammad, R. M.
- Affiliations
- Wayne State University (US)
- University of Michigan (US)
- Corresponding author
- Mohammad, Ramzi M.
- ORCID
- Venue
- European Journal of Cancer
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 46
- Issue
- 6
- Pages
- 1122-1131
- ISSN
- 0959-8049 (ISSN-L)
- PMC
- PMC4106027
- OpenAlex
- W2065016142
- Cited by
- 67
- References
- 48
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 6 · 2014: 6 · 2013: 9 · 2012: 6
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA109389, R01CA101870, U19CA113317)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2 inhibitors, cisplatin, pancreatic cancer, TP53 mutation, p73, p21, apoptosis, combination therapy, p53-MDM2 interaction, tumor xenografts
- MeSH terms
- Tumor Protein p73, Animals, Antineoplastic Combined Chemotherapy Protocols, Cisplatin, DNA-Binding Proteins, Humans, Immunohistochemistry, Indoles, Nuclear Proteins, Pancreatic Neoplasms, Spiro Compounds, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Tumor Suppressor Proteins, RNA, Small Interfering, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2
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