Schulte T W, Neckers L M
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA.
Cancer Chemother Pharmacol. 1998;42(4):273-9. doi: 10.1007/s002800050817.
Benzoquinone ansamycins are antibiotics with anticancer potential. First described as tyrosine kinase inhibitors, they are now frequently used to target HSP90 chaperone function. While herbimycin A and geldanamycin (GA) have been widely used in preclinical studies, both drugs are poor candidates for clinical trials owing to their in vivo toxicity and lack of stability. We therefore examined the biologic effects of 17-allylamino-17-demethoxygeldanamycin (17-AG), an ansamycin derivative with lower in vivo toxicity than GA.
Binding of 17-AG to HSP90 was studied in vitro using a GA-affinity beads competition assay. We analyzed the drug-induced destabilization of p185erbB2, Raf-1 and mutant p53 in SKBR3 breast cancer cells by Western blotting. The antiproliferative activities of 17-AG and GA were compared using the MTT assay.
We found that, in a similar manner to GA itself, 17-AG bound specifically to HSP90. It also led to degradation of the receptor tyrosine kinase p185erbB2, the serine/threonine kinase Raf-1 and mutant p53. Both GA and 17-AG displayed comparable antiproliferative effects in SKBR3 and MCF7 cells. Even though HSP90 binding by 17-AG was weaker than by GA, 17-AG and GA caused biologic effects in tumor cells at similar doses.
17-AG shares the important biologic features of its parent compound GA. Since 17-AG has a better toxicity profile than GA, it is an interesting candidate benzoquinone ansamycin for clinical development.
苯醌安莎霉素是一类具有抗癌潜力的抗生素。它们最初被描述为酪氨酸激酶抑制剂，现在常用于靶向热休克蛋白90（HSP90）的伴侣功能。虽然赫米霉素A和格尔德霉素（GA）已广泛用于临床前研究，但由于它们的体内毒性和缺乏稳定性，这两种药物都不是临床试验的理想选择。因此，我们研究了17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AG）的生物学效应，它是一种体内毒性低于GA的安莎霉素衍生物。
使用GA亲和珠竞争试验在体外研究17-AG与HSP90的结合。我们通过蛋白质印迹法分析了药物诱导的SKBR3乳腺癌细胞中p185erbB2、Raf-1和突变型p53的不稳定情况。使用MTT试验比较了17-AG和GA的抗增殖活性。
我们发现，与GA本身类似，17-AG特异性结合HSP90。它还导致受体酪氨酸激酶p185erbB2、丝氨酸/苏氨酸激酶Raf-1和突变型p53的降解。GA和17-AG在SKBR3和MCF7细胞中均表现出相当的抗增殖作用。尽管17-AG与HSP90的结合比GA弱，但17-AG和GA在相似剂量下对肿瘤细胞产生生物学效应。
17-AG具有其母体化合物GA的重要生物学特性。由于17-AG的毒性比GA更好，它是一种用于临床开发的有吸引力的苯醌安莎霉素候选药物。
