Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251, Hamburg, Germany.
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, 690022, Vladivostok, Russia.
Sci Rep. 2020 Aug 6;10(1):13178. doi: 10.1038/s41598-020-69751-z.
Monanchoxymycalin C (MomC) is a new marine pentacyclic guanidine alkaloid, recently isolated from marine sponge Monanchora pulchra by us. Here, anticancer activity and mechanism of action was investigated for the first time using a human prostate cancer (PCa) model. MomC was active in all PCa cell lines at low micromolar concentrations and induced an unusual caspase-independent, non-apoptotic cell death. Kinase activity screening identified activation of mitogen-activated protein kinase (MAPK) c-Jun N-terminal protein kinase (JNK1/2) to be one of the primary molecular mechanism of MomC anticancer activity. Functional assays demonstrated a specific and selective JNK1/2 activation prior to the induction of other cell death related processes. Inhibition of JNK1/2 by pretreatment with the JNK-inhibitor SP600125 antagonized cytotoxic activity of the marine compound. MomC caused an upregulation of cytotoxic ROS. However, in contrast to other ROS-inducing agents, co-treatment with PARP-inhibitor olaparib revealed antagonistic effects indicating an active PARP to be necessary for MomC activity. Interestingly, although no direct regulation of p38 and ERK1/2 were detected, active p38 kinase was required for MomC efficacy, while the inhibition of ERK1/2 increased its cytotoxicity. In conclusion, MomC shows promising activity against PCa, which is exerted via JNK1/2 activation and non-apoptotic cell death.
单氧桥海鞘灵素 C（MomC）是一种新型海洋五环胍生物碱，最近由我们从海洋海绵 Monanchora pulchra 中分离得到。在这里，首次使用人前列腺癌（PCa）模型研究了其抗癌活性和作用机制。MomC 在低微摩尔浓度下对所有 PCa 细胞系均具有活性，并诱导出一种异常的 caspase 非依赖性、非凋亡性细胞死亡。激酶活性筛选鉴定出丝裂原活化蛋白激酶（MAPK）c-Jun N-末端蛋白激酶（JNK1/2）的激活是 MomC 抗癌活性的主要分子机制之一。功能测定表明，在诱导其他细胞死亡相关过程之前，MomC 能够特异性和选择性地激活 JNK1/2。用 JNK 抑制剂 SP600125 预处理可拮抗该海洋化合物的细胞毒性。MomC 引起细胞毒性 ROS 的上调。然而，与其他诱导 ROS 的试剂相反，与 PARP 抑制剂奥拉帕尼共同处理显示出拮抗作用，表明活性 PARP 对于 MomC 活性是必需的。有趣的是，虽然没有检测到 p38 和 ERK1/2 的直接调节，但活性 p38 激酶对于 MomC 的功效是必需的，而 ERK1/2 的抑制增加了其细胞毒性。总之，MomC 对 PCa 具有有前途的活性，其通过 JNK1/2 激活和非凋亡性细胞死亡发挥作用。
