MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma.
Summary of "MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma."
This study demonstrated a pronounced synergistic growth-inhibitory effect of an MDM2 inhibitor Nutlin-3 and a proteasome inhibitor bortezomib in mantle cell lymphoma (MCL) cells regardless of TP53 mutant status and innate bortezomib sensitivity. In the mutant TP53 MCL cells which are intrinsically resistant to bortezomib, the combination of Nutlin-3/bortezomib synergistically induced cytotoxicity through the mitochondrial apoptotic pathway mediated by transcription-independent upregulation of NOXA, sequestration of MCL-1, activation of BAX, BAK, caspase-9 and -3. In the bortezomib sensitive wild-type TP53 MCL cells, the Nutlin-3/bortezomib combination caused G0/G1 cell cycle arrest followed by the increase in apoptosis induction. These findings indicate potential therapeutic efficacy of Nutlin-3/bortezomib combination for the treatment of chemorefractory MCL.
Affiliation
Department of Clinical Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Journal Details
This article was published in the following journal.
Name: Cancer letters
ISSN: 1872-7980
Pages: 161-70
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20850924
- DOI: http://dx.doi.org/10.1016/j.canlet.2010.08.015
Medical and Biotech [MESH] Definitions
Bcl-2 Homologous Antagonist-killer Protein
A multi-domain mitochondrial membrane protein and member of the bcl-2 Protein family. Bak protein interacts with TUMOR SUPPRESSOR PROTEIN P53 and promotes APOPTOSIS.
X-linked Inhibitor Of Apoptosis Protein
An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.
Staurosporine
An indolocarbazole that is a potent PROTEIN KINASE C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)
Glucagon-like Peptide 2
A 33-amino acid peptide derived from the C-terminal of PROGLUCAGON and mainly produced by the INTESTINAL L CELLS. It stimulates intestinal mucosal growth and decreased apoptosis of ENTEROCYTES. GLP-2 enhances gastrointestinal function and plays an important role in nutrient homeostasis.
Tumor Necrosis Factors
A family of proteins that were originally identified by their ability to cause NECROSIS of NEOPLASMS. Their necrotic effect on cells is mediated through TUMOR NECROSIS FACTOR RECEPTORS which induce APOPTOSIS.
PubMed Articles
Camptothecin (CPT) and Nutlin-3 caused apoptosis by increasing p53 protein and its activation in intestinal epithelial cells (IEC-6). We studied the effectiveness of these inducers on apoptosis in hum...
MDM2 inhibitor Nutlin-3a suppresses proliferation and promotes apoptosis in osteosarcoma cells.
Restoring p53 activity by inhibiting the interaction between p53 and the mouse double minutes clone 2 (MDM2) offers an attractive approach to cancer therapy. Nutlin-3a is a small-molecule inhibitor th...
Multiple myeloma (MM) is an incurable plasma cell malignancy in which p53 is rarely mutated. Thus, activation of the p53 pathway by a small molecule inhibitor of the p53-MDM2 interaction, nutlin, in M...
MYCN sensitizes neuroblastoma to the MDM2-p53 antagonists Nutlin-3 and MI-63.
MYCN amplification is a major biomarker of poor prognosis, occurring in 25-30% of neuroblastomas. MYCN has contradictory roles in promoting cell growth and sensitizing cells to apoptosis. We have rece...
Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy.
Recently much attention was given to the anticancer drug nutlin-3a, an antagonist of murine double minute 2 (MDM2) that actively inhibits p53-MDM2 interaction. Reactivating p53 function by nutlin-3a,...
Clinical Trials
Study of bortezomib administered in combination with vorinostat or placebo in patients with relapsed or refractory multiple myeloma. Histone deacetylases (HDAC) facilitate gene transcript...
Study of vorinostat in combination with bortezomib in patients with relapsed or refractory multiple myeloma after at least 2 prior treatment regimens. Histone deacetylases (HDAC) facilita...
An association between insulin resistance and mitochondrial dysfunction has been observed in aging, T2D, and in offspring of patients with T2D. It remains to be determined whether pharmac...
Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
Our central hypothesis is that oral CoQ10 is a safe and effective treatment for children with inborn errors of mitochondrial energy metabolism due to defects in specific respiratory chain...
In the absence of treatment, severe mitral valve regurgitation (MR) results in left atrium (LA) dilatation and hypertrophy, followed ultimately by left ventricular dysfunction and heart fa...
