Disease relevance of Nutlin-3

• The in vitro toxicity of nutlin-3 was similar to that of the genotoxic drug melphalan [1].
• Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL) [2].
• Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1alpha and Hdm2 [3].
• (R)-roscovitine (CYC202, Seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis [4].

High impact information on Nutlin-3

• Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells [5].
• The induction of p53 by nutlin-3 in B-CLL samples was accompanied by alterations of the mitochondrial potential and activation of the caspase-dependent apoptotic pathway [2].
• Normal human T cells showed lower sensitivity to nutlin-3 than B-CLL cells and no synergism with the genotoxic drugs [6].
• In vitro treatment with nutlin-3 induced a significant cytotoxicity on primary CD19(+) B-CLL cells, but not on normal CD19(+) B lymphocytes, peripheral-blood mononuclear cells, or bone marrow hematopoietic progenitors [2].
• Significantly, given the importance of the bone marrow microenvironment for the support and drug resistance of myeloma cells, tumor cells undergo effective apoptosis also in the presence of stromal cells, which themselves appear to tolerate exposure to nutlin-3 [1].

Biological context of Nutlin-3

• Importantly, we found that the ECT2 gene is bound by p53 in vivo in response to DNA damage and Nutlin-3 treatment [7].
• This is due to a p53-mediated down-regulation of SDF-1 mRNA, which can be exacerbated on activation of p53 by the drug Nutlin-3 [8].
• Although HdmX overexpression yielded cells resistant to Nutlin-3, ablation of HdmX expression by short hairpin RNA sensitized tumor cells to Nutlin-3-mediated cell death or arrest [9].
• Remarkably, surviving SK-N-SH cells adopted a senescence-like phenotype, whereas CLB-GA and NGP cells underwent neuronal differentiation. p53 dependence of these alternative outcomes of nutlin-3 treatment was evidenced by abrogation of the effects when p53 was knocked down by lentiviral-mediated short hairpin RNA interference [10].
• The cytoprotective effects of Nutlin-3 were not related to its regulation of p53 or consequent gene expression during cisplatin treatment [11].

Anatomical context of Nutlin-3

• We now show that Nutlin-3 efficiently induces apoptosis and diminishes long-term survival of human fibroblasts transformed in vitro by Hdm2 but not HdmX [9].
• In addition, ECT2 is down-regulated in multiple cell lines by DNA damage agents and Nutlin-3, an MDM2 antagonist, in a p53-dependent manner [7].
• In isolated mitochondria, Nutlin-3 inhibited cytochrome c release induced by Ca(2+), Bim peptide, and recombinant tBid [11].
• In an ex vivo experiment, Nutlin-3 was found to activate p53 target gene expression and apoptosis in AOM-induced tumor tissue, but not in normal adjacent mucosa [12].
• However, treatment with pharmacological inhibitors of the nuclear factor kappaB and phosphatidylinositol 3-kinase/Akt pathways sensitized endothelial cells to nutlin-3-induced apoptosis [13].

Associations of Nutlin-3 with other chemical compounds

• Furthermore, we provided evidence that inhibition of protein methyltransferases, especially arginine methyltransferases, relieve the repression of ECT2 induced by DNA damage or Nutlin-3 in a p53-dependent manner [7].
• Here we show that Nutlin-3 protected kidney cells against cisplatin-induced apoptosis [11].
• We therefore investigated the role of p53 phosphorylation on six key serine residues (Ser(6), Ser(15), Ser(20), Ser(37), Ser(46), and Ser(392)) for p53 activation using nutlin-3, a recently developed small molecule MDM2 antagonist [14].
• In SH-SY5Y cells, Bcl-XL protein overexpression protected from apoptosis induced by either nutlin-3 alone or the (R)-roscovitine plus nutlin-3 association but failed to prevent apoptosis triggered by (R)-roscovitine alone [4].
• In contrast to the chemotherapeutic agent doxorubicin, nutlin-3 showed no induction of apoptosis in vitro either in the cocultures or in isolated vascular endothelial cells, even when used at the highest concentration (10 micromol/L) [13].
• The combination of Nutlin-3 with doxorubicin or bortezomib was synergistic in wt-TP53 MCL cells [15].
• A combination of vincristine or actinomycin D with nutlin-3 enhanced the antitumor activity in RMS cell lines with wild-type p53 [16].

Gene context of Nutlin-3

• The importance of Mdm2 down-regulation in DW1/2-induced apoptosis was confirmed by treating the p53-WT cells with the p53/Mdm2 antagonist Nutlin-3 [17].
• Aside from p53, we here identify 53BP1 as a critical mediator of nutlin-3-induced cytotoxicity [18].

Analytical, diagnostic and therapeutic context of Nutlin-3

• Moreover, Western blot studies showed that (R)-roscovitine increased nutlin-3-mediated p53 stabilization [4].

References