AMF-26, a novel inhibitor of the Golgi system, targeting ADP-ribosylation factor 1 (Arf1) with potential for cancer therapy.
AMF-26, a novel inhibitor of the Golgi system, targeting ADP-ribosylation factor 1 (Arf1) with potential for cancer therapy.
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DOI：
10.1074/jbc.m111.316125
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发表时间：
2012-02-03
期刊：
影响因子：
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通讯作者：
Yamori T
中科院分区：
文献类型：
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作者：
Ohashi Y;Iijima H;Yamaotsu N;Yamazaki K;Sato S;Okamura M;Sugimoto K;Dan S;Hirono S;Yamori T
背景：高尔基体是一个潜在的肿瘤治疗靶点，但目前还没有抑制剂成为抗癌药物.结果如下：利用一种独特的生物信息学方法，我们确定了一种新的高尔基体抑制剂，AMF-26，靶向Arf 1激活，并具有强大的抗肿瘤活性。结论：AMF-26是一种很有前途的新型抗癌先导药物。意义：我们的数据表明Arf 1激活是癌症治疗的一个有希望的靶点。ADP-核糖基化因子1（Arf 1）在介导囊泡转运中起主要作用。布雷菲德菌素A（BFA）是一种已知的Arf 1-鸟嘌呤核苷酸交换因子（GEF）相互作用抑制剂，具有高度细胞毒性。因此，Arf 1与ArfGEF的相互作用是一个有吸引力的癌症治疗靶点。然而，BFA及其衍生物由于其生物利用度差，尚未超过药物开发的临床前阶段。在这里，我们的目的是确定新的抑制剂的Arf 1-ArfGEF的相互作用，显示有效的抗肿瘤活性在体内，但具有不同于BFA的化学结构。我们利用了一组39个细胞系（称为JFCR 39）加上药物敏感性数据库和比较算法，导致在一个可能的新的Arf 1-ArfGEF抑制剂AMF-26的鉴定，其结构不同于BFA。通过使用GGA 3缀合珠的下拉测定，我们证明了AMF-26抑制Arf 1活化。随后，AMF-26诱导高尔基体破坏，细胞凋亡和细胞生长抑制。计算机建模/分子动力学（MD）模拟表明，AMF-26结合到BFA结合的Arf 1-Sec 7结构域的接触表面。AMF-26影响膜运输，包括顺式高尔基体和反式高尔基体网络，以及内体系统。此外，使用AMF-26及其衍生物，我们证明了细胞生长抑制和高尔基体破坏之间存在显着的相关性。此外，口服AMF-26（83 mg/kg体重; 5天）诱导体内人乳腺癌BSY-1异种移植物完全消退，表明AMF-26是一种抑制高尔基体系统的新型抗癌候选药物，靶向Arf 1激活。
Background: Golgi is a potential target for cancer treatment, but no inhibitor became an anticancer drug. Results: Using a unique bioinformatics approach, we identified a novel Golgi inhibitor, AMF-26, targeting Arf1 activation and possessing potent antitumor activity. Conclusion: AMF-26 is a promising new anticancer drug lead. Significance: Our data indicate that Arf1 activation is a promising target for cancer treatment. ADP-ribosylation factor 1 (Arf1) plays a major role in mediating vesicular transport. Brefeldin A (BFA), a known inhibitor of the Arf1-guanine nucleotide exchange factor (GEF) interaction, is highly cytotoxic. Therefore, interaction of Arf1 with ArfGEF is an attractive target for cancer treatment. However, BFA and its derivatives have not progressed beyond the pre-clinical stage of drug development because of their poor bioavailability. Here, we aimed to identify novel inhibitors of the Arf1-ArfGEF interaction that display potent antitumor activity in vivo but with a chemical structure distinct from that of BFA. We exploited a panel of 39 cell lines (termed JFCR39) coupled with a drug sensitivity data base and COMPARE algorithm, resulting in the identification of a possible novel Arf1-ArfGEF inhibitor AMF-26, which differed structurally from BFA. By using a pulldown assay with GGA3-conjugated beads, we demonstrated that AMF-26 inhibited Arf1 activation. Subsequently, AMF-26 induced Golgi disruption, apoptosis, and cell growth inhibition. Computer modeling/molecular dynamics (MD) simulation suggested that AMF-26 bound to the contact surface of the Arf1-Sec7 domain where BFA bound. AMF-26 affected membrane traffic, including the cis-Golgi and trans-Golgi networks, and the endosomal systems. Furthermore, using AMF-26 and its derivatives, we demonstrated that there was a significant correlation between cell growth inhibition and Golgi disruption. In addition, orally administrated AMF-26 (83 mg/kg of body weight; 5 days) induced complete regression of human breast cancer BSY-1 xenografts in vivo, suggesting that AMF-26 is a novel anticancer drug candidate that inhibits the Golgi system, targeting Arf1 activation.