文章：

他汀与前药法尼基转移酶抑制剂PAMAM G4树状聚合物联合治疗对NF1恶性外周神经鞘瘤细胞培养及原位移植瘤生长的协同抑制作用

Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers

原文发布日期：23 December 2023

DOI: 10.3390/cancers16010089

类型: Article

开放获取: 是

英文摘要：

Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties of farnesyl monophosphate prodrug farnesyltransferase inhibitors (FTIs) on human NF1 malignant peripheral nerve sheath tumor (MPNST) cells are potentiated by co-treatment with lovastatin. Unfortunately, such prodrug FTIs have poor aqueous solubility. In this study, we synthesized a series of prodrug FTI polyamidoamine generation 4 (PAMAM G4) dendrimers that compete with farnesyl pyrophosphate for farnesyltransferase (Ftase) and assessed their effects on human NF1 MPNST S462TY cells. The prodrug 3-tert-butylfarnesyl monophosphate FTI-dendrimer (i.e.,IG 2) exhibited improved aqueous solubility. Concentrations ofIG 2and lovastatin (as low as 0.1 μM) having little to no effect when used singularly synergistically suppressed cell proliferation, colony formation, and induced N-RAS, RAP1A, and RAB5A deprenylation when used in combination. Combinational treatment had no additive or synergistic effects on the proliferation/viability of immortalized normal rat Schwann cells, primary rat hepatocytes, or normal human mammary epithelial MCF10A cells. Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations.

摘要翻译： 

1型神经纤维瘤病（NF1）是一种由于神经纤维蛋白的Ras-GTP酶激活活性丧失而导致RAS持续激活的疾病。RAS必须经过异戊烯化修饰（即法尼基化或香叶基香叶基化）才能正常转运和发挥功能。先前研究表明，法尼基单磷酸前药法尼基转移酶抑制剂（FTIs）对人类NF1恶性外周神经鞘瘤（MPNST）细胞的抗增殖作用可通过联合洛伐他汀治疗得到增强。然而，此类前药FTIs的水溶性较差。本研究合成了一系列能与法尼基焦磷酸竞争法尼基转移酶（Ftase）的前药FTI聚酰胺-胺第四代（PAMAM G4）树枝状聚合物，并评估了其对人类NF1 MPNST S462TY细胞的影响。前药3-叔丁基法尼基单磷酸FTI-树枝状聚合物（即IG 2）表现出改善的水溶性。单独使用几乎无效的低浓度IG 2与洛伐他汀（低至0.1 μM）联合使用时，能协同抑制细胞增殖和集落形成，并诱导N-RAS、RAP1A和RAB5A的去异戊烯化。联合治疗对永生化正常大鼠雪旺细胞、原代大鼠肝细胞或正常人乳腺上皮MCF10A细胞的增殖/活力未产生叠加或协同效应。在免疫缺陷小鼠坐骨神经中建立的S462TY异种移植瘤模型中，联合治疗（而非单一治疗）能显著抑制肿瘤生长。因此，通过偶联PAMAM G4树枝状聚合物可使法尼基单磷酸前药FTIs获得水溶性，并与临床可达到的他汀类药物浓度联用时展现出强效抗肿瘤活性。

原文链接：

Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers