Nutlin-3a, the active enantiomer of Nutlin-3, is a robust inhibitor of murine double minute (MDM2) with an IC50 of 90 nM. It blocks the interactions between MDM2 and p53, thereby stabilizing the p53 protein, and leads to the induction of cell autophagy and apoptosis. Nutlin-3a is considered promising for research into TP53 wild-type ovarian carcinomas[1][2]. Nutlin-3a serves as a therapeutic agent that inhibits MDM2, activates wild-type p53, and triggers apoptosis, making it a potential treatment for TP53 wild-type ovarian carcinomas. Three cell lines with wild-type TP53—HOC-7, OVCA429, and A2780—show high sensitivity to Nutlin-3a, with IC50 values ranging from 4 to 6 μM. SKOV3 cells present an IC50 of 38 μM in response to Nutlin-3a. Additionally, the two other ovarian clear cell lines with TP53 wild-type, TOV21G and OVAS, exhibit relatively higher sensitivity to Nutlin-3a-induced growth inhibition, with IC50 values of 14 μM and 25 μM, respectively, compared to TP53 mutant cell lines[1]. After seven days of incubation with 10 μM Nutlin-3a, there is more than 90% inhibition of NIH/3T3 cells' growth, while the proliferation of MEF cells, which lack both targets of the drug, remains unaffected. Nutlin-3a effectively halts cell-cycle progression across all cell lines, reducing the S-phase compartment to 0.2-2% and enlarging the G1- and G2/M-phase compartments, indicative of G1 and G2 arrest. The p53 targets, p21 and MDM2, show a significant increase just 3 hours after the addition of Nutlin-3a and reach peak levels at 8 hours. Nutlin-3a triggers apoptosis in approximately 60% of SJSA-1 and MHM cells after 40 hours, with the percentage rising after 60 hours to 85% and 65%, respectively[2].
Nutlin-3a 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U-2OS osteosarcoma cells
10 µM
14 days
Induced senescence rather than apoptosis
Neuro Oncol. 2012 Jul;14(7):859-69.
HCT116 p53+/+ and HCT116 p53−/− cells
10 µM
24 hours
Detected p53 accumulation and down-regulation of ING2 expression in p53 wild-type cells
Neuro Oncol. 2012 Jul;14(7):859-69.
HCT116 cells
5 µM
24 hours
Nutlin-3a treatment caused cell cycle arrest in G1 and G2 phases and promoted endoreduplication and the generation of tetraploid cells
Cancer Res. 2008 Oct 15;68(20):8260-8.
U2OS cells
5 µM
24 hours
Nutlin-3a treatment caused cell cycle arrest in G1 and G2 phases and promoted endoreduplication and the generation of tetraploid cells
Cancer Res. 2008 Oct 15;68(20):8260-8.
SW 1990 cells
10 µM
Nutlin-3a, as an MDM2 inhibitor, inhibits MDM2-p53 interactions and stabilizes the p53 protein, thereby inducing cell autophagy and apoptosis.
Mol Oncol. 2022 Mar;16(5):1200-1217.
HPAC cells
10 µM
Nutlin-3a, as an MDM2 inhibitor, inhibits MDM2-p53 interactions and stabilizes the p53 protein, thereby inducing cell autophagy and apoptosis.
Mol Oncol. 2022 Mar;16(5):1200-1217.
HCT116 p21 KO cells
10 μM
8 h
Nutlin-3a treatment led to stabilization of p53 and restored the induction of PUMA in the presence of either growth factor.
Oncogene. 2010 Mar 18;29(11):1622-32.
ALST cells
10 μM
24 h
To test the activation of WT TP53 by Nutlin-3a, results showed that Nutlin-3a increased WT TP53 activity.
Neoplasia. 2015 Oct;17(10):789-803.
OVCA433 cells
10 μM
24 h
To test the activation of WT TP53 by Nutlin-3a, results showed that Nutlin-3a increased WT TP53 activity.
Neoplasia. 2015 Oct;17(10):789-803.
OVCA420 cells
20 μM
24 h
To test the effect of Nutlin-3a on cell viability, results showed that OVCA420 cells were less sensitive to Nutlin-3a.
Neoplasia. 2015 Oct;17(10):789-803.
OVCAR3 cells
20 μM
24 h
To test the effect of Nutlin-3a on cell viability, results showed that OVCAR3 cells were less sensitive to Nutlin-3a.
Neoplasia. 2015 Oct;17(10):789-803.
HepG2 cells
10 µM
Nutlin-3a treatment increased ApoB expression and secretion and reduced lipid accumulation.
Adv Sci (Weinh). 2022 Jul;9(20):e2200742.
Primary hepatocytes
10 µM
Nutlin-3a treatment increased ApoB expression and secretion and reduced lipid accumulation.
Adv Sci (Weinh). 2022 Jul;9(20):e2200742.
LNCaP cells
0.5 μM
5 days
Nutlin-3a activates p53 signaling, inhibits LNCaP cell growth, and induces cell cycle arrest and apoptosis.
Mol Cancer. 2011 May 3;10:49.
22Rv1 cells
5 μM
48 h
Nutlin-3a combined with androgen deprivation enhanced the apoptotic response in 22Rv1 cells.
Mol Cancer. 2011 May 3;10:49.
DU145 cells
5 μM
48 h
No significant increase in apoptosis was observed in DU145 cells treated with Nutlin-3a.
Mol Cancer. 2011 May 3;10:49.
MCF-7 cells
8 μM
12 h
Using GRO-seq analysis, the production of enhancer RNAs (eRNAs) induced by nutlin-3a was detected, revealing p53-regulated enhancer regions.
Nat Commun. 2015 Mar 27;6:6520.
MCF-7 cells
8 μM
12 h
Through RNA sequencing, 194 nutlin-3a-responsive long non-coding RNAs (lncRNAs) were identified, and the importance of LED in the p53 transcriptional response was validated.
Nat Commun. 2015 Mar 27;6:6520.
PA-1 cells
40 μM
48 h
To evaluate the effect of Nutlin-3a on the p53 signaling pathway, results showed upregulation of p53 expression
Theranostics. 2017 Oct 13;7(18):4566-4576.
MCF-7 cells
40 μM
48 h
To evaluate the effect of Nutlin-3a on the p53 signaling pathway, results showed upregulation of p53 expression
Theranostics. 2017 Oct 13;7(18):4566-4576.
MDA-MB-231
15 µM
5 days
To evaluate the inhibitory effects of Nutlin-3a and carboplatin on cell proliferation, results showed that the combination of Nutlin-3a and carboplatin had a synergistic effect, significantly inhibiting cell proliferation
Mol Cancer Ther. 2015 Dec;14(12):2850-63.
TMD231
15 µM
5 days
To evaluate the inhibitory effects of Nutlin-3a and carboplatin on cell proliferation, results showed that the combination of Nutlin-3a and carboplatin had a synergistic effect, significantly inhibiting cell proliferation
Mol Cancer Ther. 2015 Dec;14(12):2850-63.
MDA-MB-468
15 µM
5 days
To evaluate the inhibitory effects of Nutlin-3a and carboplatin on cell proliferation, results showed that the combination of Nutlin-3a and carboplatin had a synergistic effect, significantly inhibiting cell proliferation
Mol Cancer Ther. 2015 Dec;14(12):2850-63.
MCF-7
15 µM
5 days
To evaluate the inhibitory effects of Nutlin-3a and carboplatin on cell proliferation, results showed that the combination of Nutlin-3a and carboplatin had a synergistic effect, significantly inhibiting cell proliferation
Mol Cancer Ther. 2015 Dec;14(12):2850-63.
Nutlin-3a 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
C-Myc-deficient mice
Gavage
200 mg/kg
Twice daily for 3 days, with the final dose 3 h before irradiation
Nutlin-3a treatment restored the apoptotic response in c-Myc-deficient mice, demonstrating that restoration of p53 function, via Nutlin treatment, is sufficient to rescue the blocked apoptosis phenotype in c-Myc-deficient enterocytes.
Cell Death Differ. 2014 Jun;21(6):956-66
Nude mice
Pancreatic cancer xenograft model
Intratumoral injection
100 mg/kg
Injected on days 1, 4, and 7, lasting for 21 days
Nutlin-3a, as an MDM2 inhibitor, enhanced the antipancreatic cancer effect of USP22 overexpression, significantly slowing tumor growth.
Mol Oncol. 2022 Mar;16(5):1200-1217.
Mice
Whole body radiation (WBR) model
Intraperitoneal injection
10 mg/kg
1 hour after radiation
Nutlin-3a treatment restored the induction of PUMA and p53 in the presence of growth factors and significantly blocked the growth factor-mediated suppression of radiation-induced apoptosis.
Oncogene. 2010 Mar 18;29(11):1622-32.
Mice
CDAHFD-induced steatohepatitis model
Intraperitoneal injection
10 mg/kg
Twice daily for 1-2 weeks
Nutlin-3a treatment alleviated CDAHFD-induced steatohepatitis by upregulating ApoB-mediated TG-VLDL secretion.
Adv Sci (Weinh). 2022 Jul;9(20):e2200742.
Nude mice
LNCaP xenograft model
Oral
200 mg/kg
Twice daily for 14 days
Nutlin-3a combined with androgen deprivation significantly enhanced antitumor activity, leading to complete tumor regression and dramatically increased survival in mice.
Mol Cancer. 2011 May 3;10:49.
Nude mice
PA-1 xenograft model
Intratumoral injection
10 mg/kg
Every other day for 3 weeks
To evaluate the tumor growth inhibitory effect of Nutlin-3a, results showed a tumor growth inhibition rate of 30%
Theranostics. 2017 Oct 13;7(18):4566-4576.
Mice
TMD231 orthotopic mammary fat pad model
Oral and intraperitoneal injection
200 mg/kg
Twice weekly for 4 weeks
To evaluate the inhibitory effects of Nutlin-3a and carboplatin combination on primary tumor growth and lung metastasis, results showed that the combination treatment significantly inhibited tumor growth and lung metastasis with minimal toxicity to normal tissues
Mol Cancer Ther. 2015 Dec;14(12):2850-63.
Nutlin-3a 动物研究
Animal study
Nutlin-3a proves to be effective across all models, achieving an average tumor growth inhibition of ≥98%. It diminishes xenograft growth in a dose-responsive manner, with the highest administered dose of 200 mg/kg resulting in significant tumor reduction, including eight partial and one complete regressions. Treatment with Nutlin-3a in established SJSA-1 and MHM osteosarcoma xenografts leads to extensive tumor regression[2].
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