Kedei Noemi, Kraft Matthew B, Keck Gary E, Herald Cherry L, Melody Noeleen, Pettit George R, Blumberg Peter M
†Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
‡Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
J Nat Prod. 2015 Apr 24;78(4):896-900. doi: 10.1021/acs.jnatprod.5b00094. Epub 2015 Mar 26.
Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the bryostatin 1 structure is largely sufficient for bryostatin 1-like activity, provided the molecule also possesses an appropriate PKC binding domain.
苔藓抑素1是一种从滨螺中分离出的复杂大环内酯，已成为癌症多项临床试验的研究对象。尽管苔藓抑素1在体外作为蛋白激酶C（PKC）的激活剂发挥作用，但矛盾的是，它能拮抗对典型PKC激活剂佛波酯的大多数反应。苔藓抑素1结构的下半部分已被证明足以使其与PKC结合。相比之下，我们之前已表明，苔藓抑素1结构的上半部分对于其拮抗佛波酯反应的独特生物学行为是必需的。海兔抑素1包含一个与苔藓抑素1相似的上半部分以及一个赋予PKC结合能力的独特下半部分。我们在此报告，海兔抑素1对U937早幼粒细胞白血病细胞的生物学活性类似苔藓抑素1，而非类似佛波酯。我们得出结论，只要分子还具有合适的PKC结合结构域，苔藓抑素1结构的上半部分在很大程度上足以产生类似苔藓抑素1的活性。
