Nutlin-3a chiral, an active isomer of Nutlin-3, is a murine double microbody 2 (MDM2) antagonist with IC50 value of 0.09μM . Nutlin-3a chiral inhibits MDM2-p53 interaction and activates wild-type p53, inducing cell cycle arrest and apoptosis[2].
Incubation with 10 μm Nutlin-3a chiral for 7 days resulted in > 90% inhibition of NIH/3T3 cell growth but did not affect MEF proliferation, in which both targets of the drug were eliminated[3].
Nutlin-3a chiral was able to increase the sensitivity to BBR and certain NAX compounds. The effects of Nutlin-3a chiral were usually more substantial in those cells containing an introduced WT TP53 gene[6]. Nutlin-3a chiral binds MDM2 in the TP53-bindingpocket, thereby interfering with MDM2-directed TP53 degradation. This has been shown to cause cell cycle arrest, growth inhibitionand apoptosis in both solid tumors and lymphoid neoplasms.In mantle cell lymphoma(MCL), Nutlin-3a chiral can inhibit cell growth and activate apoptosis in bothwt-TP53(IC50 of 1 to 10μM) and mt-TP53(IC50 of 22.5μM) cells[4]. Nutlin-3a chiral can also effectcell cycle in gastric cancer cell lines. It induces G1 arrest inMKN-45 and SNU-1 cell lines[5].LA-N-5(human neuroblastoma) and SMS-KCNR cells pretreated with Nutlin-3a chiral were significantly more susceptible to DNAM-1-engineered NK cells than NK cells transfected with the empty vector suggesting that the combined use of DNAM-1-chimeric receptor-engineered NK cells and Nutlin-3a chiral may represent a novel therapeutic approach for the treatment of solid tumors, such as NB, carrying dysfunctional p53[7].
In Sjsa-1 tumor-bearing nude mice, Nutlin-3a chiral inhibited xenograft growth in a dose-dependent manner, with the highest dose (200 mg/kg) showing significant tumor shrinkage[3].
参考文献:
[1]: Yang X, Liu J, et,al. miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities. Oncogenesis. 2021 Feb 12;10(2):15. doi: 10.1038/s41389-021-00304-3. PMID: 33579899; PMCID: PMC7881152.
[2]: Crane EK, Kwan SY, et,al. Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas. PLoS One. 2015 Aug 6;10(8):e0135101. doi: 10.1371/journal.pone.0135101. PMID: 26248031; PMCID: PMC4527847.
[3]: Tovar C, Rosinski J, et,al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1888-93. doi: 10.1073/pnas.0507493103. Epub 2006 Jan 27. PMID: 16443686; PMCID: PMC1413632.
[4]: Roscoe I, Parker M, et,al. Human Serum Albumin and the p53-Derived Peptide Fusion Protein Promotes Cytotoxicity Irrespective of p53 Status in Cancer Cells. Mol Pharm. 2018 Nov 5;15(11):5046-5057. doi: 10.1021/acs.molpharmaceut.8b00647. Epub 2018 Oct 10. PMID: 30226785.
[5]: Chen R, Zhou J, et,al. A Fusion Protein of the p53 Transaction Domain and the p53-Binding Domain of the Oncoprotein MdmX as an Efficient System for High-Throughput Screening of MdmX Inhibitors. Biochemistry. 2017 Jun 27;56(25):3273-3282. doi: 10.1021/acs.biochem.7b00085. Epub 2017 Jun 14. PMID: 28581721.
[6]: Abrams SL, Akula SM, et,al. Effects of the MDM2 inhibitor Nutlin-3a on sensitivity of pancreatic cancer cells to berberine and modified berberines in the presence and absence of WT-TP53. Adv Biol Regul. 2022 Jan;83:100840. doi: 10.1016/j.jbior.2021.100840. Epub 2021 Nov 23. PMID: 34866036.
[7]: Focaccetti C, Benvenuto M, et,al. DNAM-1-chimeric receptor-engineered NK cells, combined with Nutlin-3a, more effectively fight neuroblastoma cells in vitro: a proof-of-concept study. Front Immunol. 2022 Jul 28;13:886319. doi: 10.3389/fimmu.2022.886319. PMID: 35967339; PMCID: PMC9367496.
Nutlin-3a 手性是 Nutlin-3 的活性异构体，是鼠类双微体 2 (MDM2) 拮抗剂，IC50 值为 0.09μM。 Nutlin-3a 手性抑制 MDM2-p53 相互作用并激活野生型 p53，诱导细胞周期停滞和细胞凋亡[2]。
与 10 μm Nutlin-3a 手性孵育 7 天产生 >； 90%抑制NIH/3T3细胞生长但不影响MEF增殖，药物的两个靶点均被消除[3]。
Nutlin-3a 手性能够提高对 BBR 和某些 NAX 化合物的敏感性。 Nutlin-3a 手性的作用通常在那些含有引入的 WT TP53 基因的细胞中更为显着[6]。 Nutlin-3a 手性结合 TP53 结合袋中的 MDM2，从而干扰 MDM2 定向的 TP53 降解。这已被证明会导致实体瘤和淋巴肿瘤的细胞周期停滞、生长抑制和细胞凋亡。在套细胞淋巴瘤 (MCL) 中，Nutlin-3a 手性可抑制细胞生长并激活 wt-TP53 的细胞凋亡（IC50 为 1 至 10μM ) 和 mt-TP53(IC50 为 22.5μM) 细胞[4]。 Nutlin-3a 手性也可以影响胃癌细胞系的细胞周期。它在 MKN-45 和 SNU-1 细胞系中诱导 G1 期阻滞[5]。用 Nutlin-3a 手性预处理的 LA-N-5（人神经母细胞瘤）和 SMS-KCNR 细胞对 DNAM 更敏感-1 工程 NK 细胞比用空载体转染的 NK 细胞表明 DNAM-1 嵌合受体工程 NK 细胞和 Nutlin-3a 手性的联合使用可能代表治疗实体瘤的新治疗方法，例如注意，携带功能失调的 p53[7]。
在 Sjsa-1 荷瘤裸鼠中，Nutlin-3a 手性以剂量依赖的方式抑制异种移植物的生长，最高剂量（200 mg/kg）显示出显着的肿瘤缩小[3].
| Cell experiment [1]: | |
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Cell lines |
Mouse NIH/3T3 fibroblasts |
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Preparation Method |
Exponentially growing mouse NIH/3T3 fibroblasts (wt-TP53) were incubated for 7 days in the presence of Nutlin-3a chiral and stained live by acridine orange. |
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Reaction Conditions |
10 μM Nutlin-3a chiral for 7 days |
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Applications |
When tested the activity of Nutlin-3a chiral, on exponentially proliferating mouse NIH/3T3 fibroblasts that express wild-type p53, Seven days of incubation with 10 μM Nutlin-3a chiral led to >90% inhibition of NIH/3T3 cells growth. |
| Animal experiment [2]: | |
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Animal models |
Sjsa-1 tumor-bearing nude mice |
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Preparation Method |
Mice were given an oral dose of 200 mg/kg Nutlin-3a chiral twice daily for 2 weeks (LnCaP and 22Rv1) or 3 weeks (MHM) |
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Dosage form |
200mg/kg Nutlin-3a chiral for 2 or 3 weeks |
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Applications |
Nutlin-3a chiral inhibited xenograft growth in a dose-dependent manner, with the highest dose (200 mg/kg) showing significant tumor shrinkage |
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参考文献: [1]. Tovar C, Rosinski J, et,al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1888-93. doi: 10.1073/pnas.0507493103. Epub 2006 Jan 27. PMID: 16443686; PMCID: PMC1413632. |
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