Research Papers:

Network Modeling of MDM2 Inhibitor-Oxaliplatin Combination Reveals Biological Synergy in wt-p53 solid tumors

Asfar S. Azmi, Sanjeev Banerjee, Shadan Ali, Zhiwei Wang, Bin Bao, Frances WJ Beck, Anthony F. Shields, Philip Philip, Fazlul H. Sarkar _ and Ramzi M. Mohammad

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Oncotarget. 2011; 2:378-392. https://doi.org/10.18632/oncotarget.269

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Asfar S. Azmi1, Sanjeev Banerjee1, Shadan Ali1, Zhiwei Wang1, Bin Bao1, Frances W.J. Beck2, Main Maitah2, Minsig Choi2, Tony F. Shields2, Philip A. Philip2, Fazlul H. Sarkar1, Ramzi M. Mohammad2

1Department of Pathology, Wayne State University School of Medicine

2Departments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan

Keywords: MDM2 and p53, MI-219, oxaliplatin Network Modeling

Received: April 28, 2011; Accepted: May 11, 2011; Published: May 16, 2011;


Fazlul H Sarkar, e-mail:

Ramzi M. Mohammad, e-mail:


Earlier we had shown that the MDM2 inhibitor (MI-219) belonging to the spiro-oxindole family can synergistically enhance the efficacy of platinum chemotherapeutics leading to 50% tumor free survival in a genetically complex pancreatic ductal adenocarcinoma (PDAC) xenograft model. In this report, we have taken a systems and network modeling approach in order to understand central mechanisms behind MI219-oxaliplatin synergy with validation in PDAC, colon and breast cancer cell lines. Microarray profiling of drug treatments (MI-219, oxaliplatin or their combination) in capan-2 cells reveal a similar unique set of gene alterations that is duplicated in other solid tumor cells. As single agent, MI-219 or oxaliplatin induced alterations in 48 and 761 genes respectively. The combination treatment resulted in 767 gene alterations with emergence of 286 synergy unique genes. Ingenuity network modeling of combination and synergy unique genes showed the crucial role of five key local networks CREB, CARF, EGR1, NF-kB and E Cadherin. The network signatures were validated at the protein level in all three cell lines. Individually silencing central nodes in these five hubs resulted in abrogation of MI-219-oxaliplatin activity confirming their critical role in aiding p53 mediated apoptotic response. We anticipate that our MI219-oxaliplatin network blueprints can be clinically translated in the rationale design and application of this unique therapeutic combination in a genetically pre-defined subset of patients.

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