Stevenson Christopher S, Capper Elizabeth A, Roshak Amy K, Marquez Brian, Eichman Chris, Jackson Jeffrey R, Mattern Michael, Gerwick William H, Jacobs Robert S, Marshall Lisa A
Department of Ecology, Evolution, and Marine Biology, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
J Pharmacol Exp Ther. 2002 Nov;303(2):858-66. doi: 10.1124/jpet.102.036350.
Marine natural products provide a rich source of chemical diversity that can be used to design and develop new, potentially useful therapeutic agents. We report here that scytonemin, a pigment isolated from cyanobacteria, is the first described small molecule inhibitor of human polo-like kinase, a serine/threonine kinase that plays an integral role in regulating the G(2)/M transition in the cell cycle. Scytonemin inhibited polo-like kinase 1 activity in a concentration-dependent manner with an IC(50) of 2 microM against the recombinant enzyme. Biochemical analysis showed that scytonemin reduced GST-polo-like kinase 1 activity in a time-independent fashion, suggesting reversibility, and with a mixed-competition mechanism with respect to ATP. Although scytonemin was less potent against protein kinase A and Tie2, a tyrosine kinase, it did inhibit other cell cycle-regulatory kinases like Myt1, checkpoint kinase 1, cyclin-dependent kinase 1/cyclin B, and protein kinase Cbeta2 with IC(50) values similar to that seen for polo-like kinase 1. Consistent with these effects, scytonemin effectively attenuated, without chemical toxicity, the growth factor- or mitogen-induced proliferation of three cell types commonly implicated in inflammatory hyperproliferation. Similarly, scytonemin (up to 10 microM) was not cytotoxic to nonproliferating endotoxin-stimulated human monocytes. In addition, Jurkat T cells treated with scytonemin were induced to undergo apoptosis in a non-cell cycle-dependent manner consistent with its activities on multiple kinases. Here we propose that scytonemin's dimeric structure, unique among natural products, may be a valuable template for the development of more potent and selective kinase inhibitors used for the treatment of hyperproliferative disorders.
海洋天然产物提供了丰富的化学多样性来源，可用于设计和开发新的、可能有用的治疗剂。我们在此报告，从蓝细菌中分离出的一种色素——藻青素，是首个被描述的人源polo样激酶小分子抑制剂，polo样激酶是一种丝氨酸/苏氨酸激酶，在调节细胞周期的G(2)/M转换中起不可或缺的作用。藻青素以浓度依赖的方式抑制polo样激酶1的活性，对重组酶的IC(50)为2微摩尔。生化分析表明，藻青素以与时间无关的方式降低GST-polo样激酶1的活性，提示其具有可逆性，且对ATP呈混合竞争机制。尽管藻青素对蛋白激酶A和酪氨酸激酶Tie2的抑制作用较弱，但它确实能抑制其他细胞周期调节激酶，如Myt1、关卡激酶1、细胞周期蛋白依赖性激酶1/细胞周期蛋白B和蛋白激酶Cβ2，其IC(50)值与polo样激酶1相似。与这些作用一致，藻青素能有效减轻三种通常与炎症性过度增殖有关的细胞类型在生长因子或有丝分裂原诱导下的增殖，且无化学毒性。同样，高达10微摩尔的藻青素对未增殖的内毒素刺激的人单核细胞无细胞毒性。此外，用藻青素处理的Jurkat T细胞被诱导以非细胞周期依赖的方式发生凋亡，这与其对多种激酶的作用一致。在此我们提出，藻青素独特的二聚体结构在天然产物中独一无二，可能是开发用于治疗过度增殖性疾病的更有效、更具选择性的激酶抑制剂的宝贵模板。
