Shaikenov T E, Adekenov S M, Williams R M, Prashad N, Baker F L, Madden T L, Newman R
NuOncology Labs Inc., Houston, TX 77054, USA.
Oncol Rep. 2001 Jan-Feb;8(1):173-9. doi: 10.3892/or.8.1.173.
Arglabin [1(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),11(13)-dien-6, 12-olide], a sesquiterpene gamma-lactone is isolated from Artemisia glabella, a species of wormwood endemic to the Karaganda region of Kazakstan. The compound has been modified to render it water-soluble through addition of a dimethylaminohydrochloride group to the C(13) carbohydride moiety to yield Arglabin-DMA. Arglabin-DMA is a registered antitumor substance in the Republic of Kazakstan. Previously, we have shown that this compound prevents protein farnesylation without altering geranylgeranylation. We now report that Arglabin-DMA inhibits the incorporation of [(3)H]farnesylpyrophosphate into human H-ras protein by FTase with an IC(50) of no greater than 25 microM. Kinetic studies show that the phosphorylated form of this compound competitively inhibits the binding of farnesyl diphosphate to FTase. This mechanism of action is different from other reported peptidomimetic FTIs which lower the affinity of ras protein to FTase. Our in vitro studies confirm that Arglabin-DMA inhibits post-translational modification of ras protein in cells. Arglabin-DMA inhibits anchorage-dependent proliferation of NB cells (IC50=10 microg/ml) and inhibits anchorage-independent growth of NB and KNRK cells with about the same IC(50). Soft-agar colony formation assay of H-ras and K-ras transformed cells show IC(50)s to be 2 and 5 microg/ml, respectively. In primary cultures of human tumor cells, Arglabin-DMA inhibits cell proliferation of a variety of tumor types with IC(90)s in the range of 0.85 to 5.0 microg/ml. Because of these pharmacologic properties, we propose that Arglabin-DMA is suitable for the treatment of ras related malignancies.
阿格拉宾[1(R),10(S)-环氧-5(S),5(S),7(S)-愈创木-3(4),11(13)-二烯-6,12-内酯]，一种倍半萜γ-内酯，是从哈萨克斯坦卡拉干达地区特有的蒿属植物光果蒿中分离得到的。该化合物已通过在C(13)碳水化合物部分添加二甲基氨基盐酸基团进行修饰，使其具有水溶性，从而得到阿格拉宾-DMA。阿格拉宾-DMA是哈萨克斯坦共和国注册的抗肿瘤物质。此前，我们已经表明该化合物可防止蛋白质法尼基化，而不改变香叶基香叶基化。我们现在报告，阿格拉宾-DMA抑制FTase将[(3)H]法尼基焦磷酸掺入人H-ras蛋白，IC(50)不大于25μM。动力学研究表明，该化合物的磷酸化形式竞争性抑制法尼基二磷酸与FTase的结合。这种作用机制不同于其他报道的肽模拟物FTIs，后者降低了ras蛋白与FTase的亲和力。我们的体外研究证实，阿格拉宾-DMA抑制细胞中ras蛋白的翻译后修饰。阿格拉宾-DMA抑制NB细胞的贴壁依赖性增殖(IC50=10μg/ml)，并以大致相同的IC(50)抑制NB和KNRK细胞的非贴壁依赖性生长。H-ras和K-ras转化细胞的软琼脂集落形成试验显示IC(50)分别为2和5μg/ml。在人肿瘤细胞的原代培养中，阿格拉宾-DMA抑制多种肿瘤类型的细胞增殖，IC(90)在0.85至5.0μg/ml范围内。由于这些药理特性，我们认为阿格拉宾-DMA适用于治疗与ras相关的恶性肿瘤。
