Nutlin-3a

MCE 国际站：Nutlin-3a

产品活性：Nutlin-3a (Rebemadlin) 是 Nutlin-3 的活性对映体，是一种有效的 MDM2 抑制剂。Nutlin-3a 可抑制 MDM2-p53 相互作用，稳定 p53 蛋白，从而诱导细胞自噬 (autophagy) 和凋亡 (apoptosis)。Nutlin-3a 有潜力用于 TP53 野生型卵巢癌的研究。

研究领域：Apoptosis | Metabolic Enzyme/Protease | Autophagy

作用靶点：MDM-2/p53 | E1/E2/E3 Enzyme | Autophagy | Apoptosis

In Vitro: Nutlin-3a is a therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis-as a therapeutic compound for TP53 wild-type ovarian carcinomas. Three cell lines (HOC-7, OVCA429 and A2780) with wild-type TP53 are highly sensitive to Nutlin-3a (IC₅₀=4 to 6 μM). SKOV3 cells have an IC₅₀ of 38 μM to Nutlin-3a. The two remaining ovarian clear cell lines (TOV21G and OVAS), both with TP53 wild-type, are relatively more sensitive to growth inhibition with Nutlin-3a (IC₅₀=14 and 25 μm respectively) than the TP53 mutant cell lines. Nutlin-3a is the active enantiomer of Nutlin-3. Nutlin-3a is a highly selective MDM2 antagonist and p53 inducer. Seven days of incubation with 10 μM Nutlin-3a leads to >90% inhibition of NIH/3T3 cells’growth but does not affect the proliferation of MEF in which both targets of the drug are eliminated. Nutlin-3a effectively arrestes cell-cycle progression in all cell lines, depleting the S-phase compartment to 0.2-2% and increasing the G₁- and G₂/M-phase compartments, indicating G₁ and G₂ arrest. The p53 targets p21 and MDM2 are elevated significantly 3 h after Nutlin-3a addition and reach maximal levels at 8 h. Nutlin-3a induces apoptosis in ≈60% of SJSA-1 and MHM cells after 40 h, which increase further after 60 h (85% and 65%, respectively).

In Vivo: Nutlin-3a is efficacious in all models with average tumor growth inhibition ≥98%. Nutlin-3a suppresses xenograft growth in a dose-dependent fashion with the highest dose (200 mg/kg) showing a substantial tumor shrinkage (eight partial and one full regressions). The established SJSA-1 and MHM osteosarcoma xenografts with Nutlin-3a causes extensive tumor regression.

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