Inhibition of the MDM2 E3 Ligase induces apoptosis and autophagy in wild-type and mutant p53 models of multiple myeloma, and acts synergistically with ABT-737.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Apoptosis/*drug effects ; Autophagy/*drug effects ; Biphenyl Compounds/*pharmacology ; Multiple Myeloma/*pathology ; Mutation/*genetics ; Nitrophenols/*pharmacology ; Proto-Oncogene Proteins c-mdm2/*antagonists & inhibitors ; Sulfonamides/*pharmacology ; Tumor Suppressor Protein p53/*metabolism; Animals ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Drug Synergism ; Indoles/pharmacology ; Mice, Inbred NOD ; Mice, SCID ; Piperazines/pharmacology ; Proto-Oncogene Proteins c-mdm2/metabolism ; Spiro Compounds/pharmacology

Intracellular proteolytic pathways have been validated as rational targets in multiple myeloma with the approval of two proteasome inhibitors in this disease, and with the finding that immunomodulatory agents work through an E3 ubiquitin ligase containing Cereblon. Another E3 ligase that could be a rational target is the murine double minute (MDM) 2 protein, which plays a role in p53 turnover. A novel inhibitor of this complex, MI-63, was found to induce apoptosis in p53 wild-type myeloma models in association with activation of a p53-mediated cell death program. MI-63 overcame adhesion-mediated drug resistance, showed anti-tumor activity in vivo, enhanced the activity of bortezomib and lenalidomide, and also overcame lenalidomide resistance. In mutant p53 models, inhibition of MDM2 with MI-63 also activated apoptosis, albeit at higher concentrations, and this was associated with activation of autophagy. When MI-63 was combined with the BH3 mimetic ABT-737, enhanced activity was seen in both wild-type and mutant p53 models. Finally, this regimen showed efficacy against primary plasma cells from patients with newly diagnosed and relapsed/refractory myeloma. These findings support the translation of novel MDM2 inhibitors both alone, and in combination with other novel agents, to the clinic for patients with multiple myeloma.

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P30 CA016672 United States CA NCI NIH HHS; P50 CA142509 United States CA NCI NIH HHS

0 (ABT-737)
0 (Biphenyl Compounds)
0 (Indoles)
0 (MI-63 compound)
0 (Nitrophenols)
0 (Piperazines)
0 (Spiro Compounds)
0 (Sulfonamides)
0 (Tumor Suppressor Protein p53)
EC 2.3.2.27 (MDM2 protein, human)
EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)

Date Created: 20140903 Date Completed: 20150518 Latest Revision: 20211021

20221213

PMC4151993

10.1371/journal.pone.0103015

25181509