(±)-Nutlin-3 is a potent and selective MDM2 antagonist with IC50 value of 0.09μM[1]. Mouse double minute 2 homolog (MDM2) is an important negative regulator of the tumor suppressor p53, and disrupting the p53-MDM2 interaction activates p53 to inhibit tumor growth[2]. (±)-Nutlin-3 is usually used in the study of tumorigenesis mechanisms and p53 function[3].
In vitro, (±)-Nutlin-3 (10μM; 24h) reduced clonogenic survival of 22RV1 prostate cancer cells, stabilized p53 and p21 proteins, induced G1 arrest and slightly increased apoptosis[4]. (±)-Nutlin-3 (10μM; 48h) markedly induced apoptosis in 29/30 primary B-CLL samples (Annexin-V positivity, loss of ΔΨm, Caspase-3 activation and PARP cleavage), while up-regulating p53, p21, TRAIL-R2 and PIG3 expression, and showed minimal toxicity toward normal CD19⁺ B cells and CD34⁺ hematopoietic progenitors[5].
In vivo, (±)-Nutlin-3 (150mg/kg; p.o.; twice daily for 21 days) combined with Inauhzin (15mg/kg; i.p.; once daily for 21 days) significantly reduced HCT116p53⁺/⁺ xenograft tumor volume in nude mice by 60%, elevated intratumoral p53 and PUMA protein levels, increased TUNEL-positive apoptotic cells and decreased BrdU-labeled proliferating cells[6]. (±)-Nutlin-3 (200mg/kg; p.o.; twice daily for 3 weeks) markedly suppressed primary tumor growth in UKF-NB-3rDOX20 (WT p53) multidrug-resistant neuroblastoma xenografts in nude mice, decreased hepatic and pulmonary MYCN DNA and mRNA levels, reduced metastatic foci and enhanced intratumoral Caspase-3 activity, whereas no effect was observed in p53-mutant UKF-NB-3rVCR10 xenografts[7].
References:
[1] Yu Z, Zhuang C, Wu Y, et al. Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors. Int J Mol Sci. 2014;15(9):15741-15753.
[2] Shinohara T, Uesugi M. In-vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Tanpakushitsu Kakusan Koso. 2007;52(13 Suppl):1816-1817.
[3] Secchiero P, Bosco R, Celeghini C, Zauli G. Recent advances in the therapeutic perspectives of Nutlin-3. Curr Pharm Des. 2011;17(6):569-577.
[4] Supiot S, Hill RP, Bristow RG. Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53. Mol Cancer Ther. 2008;7(4):993-999.
[5] Secchiero P, Barbarotto E, Tiribelli M, et al. Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006;107(10):4122-4129.
[6] Zhang Y, Zhang Q, Zeng SX, Zhang Y, Mayo LD, Lu H. Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth. Cancer Biol Ther. 2012;13(10):915-924.
[7] Van Maerken T, Ferdinande L, Taildeman J, et al. Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J Natl Cancer Inst. 2009;101(22):1562-1574.
(±)-Nutlin-3是一种强效且选择性的MDM2拮抗剂，其IC50为0.09μM[1]。鼠双微体 2（MDM2）是抑癌蛋白p53的重要负调控因子，阻断p53-MDM2相互作用可激活p53，从而抑制肿瘤生长[2]。(±)-Nutlin-3常用于肿瘤发生机制及p53功能研究[3]。
在体外，(±)-Nutlin-3（10μM；24h）可降低22RV1前列腺癌细胞的克隆存活率，稳定p53和p21蛋白，诱导G1期阻滞并轻度增加细胞凋亡[4]。(±)-Nutlin-3（10μM；48h）可显著诱导29/30例原发性B-CLL样本发生凋亡（表现为Annexin-V 阳性、线粒体膜电位丧失、Caspase-3激活及PARP裂解），上调p53、p21、TRAIL-R2及PIG3表达，而对正常CD19⁺B细胞及CD34⁺造血祖细胞毒性极低[5]。
在体内，(±)-Nutlin-3（150mg/kg；口服；每日2次，连续 21天）联合Inauhzin（15mg/kg；腹腔注射；每日1次，连续21天）使裸鼠HCT116-p53⁺/⁺异种移植瘤体积显著缩小60%，提升肿瘤内p53与PUMA蛋白水平，增加TUNEL 阳性凋亡细胞并减少BrdU标记的增殖细胞比例[6]。(±)-Nutlin-3（200mg/kg；口服；每日2次，连续3周）显著抑制裸鼠UKF-NB-3rDOX20（WT p53）耐药神经母细胞瘤异种移植瘤的原发肿瘤生长，降低肝脏和肺脏的MYCN DNA和mRNA水平，减少转移灶数目并增强肿瘤内Caspase-3活性；而在p53突变的 UKF-NB-3rVCR10异种移植瘤中未见上述效应[7]。