Spliceosomes mediate the processing of pre-mRNA into mature mRNA.[1],[2] Each spliceosome is a multiunit complex containing several proteins and RNA molecules that work in unison to repeatedly cleave and rejoin segments of mRNA.[1],[3] Pladienolide B is a macrocyclic lactone that selectively binds splicing factor 3b and inhibits mRNA splicing.[4],[5] Through this action, pladienolide B potently blocks the growth of proliferating cells with mean IC50 values of 1.6 nM for six gastric cancer cell lines.[6],[7] In xenograft tumors generated in mice using human cancer cells, pladienolide B blocks mRNA splicing and induces apoptosis, clearing tumors within two weeks after treatment.[7]
剪接体介导 pre-mRNA 加工成成熟 mRNA。[1]、[2] 每个剪接体都是一个多单元复合体，包含多个蛋白质和 RNA 分子，它们协同工作以反复切割和重新连接 mRNA 片段。 [1]、[3] Pladienolide B 是一种大环内酯，可选择性结合剪接因子 3b 并抑制 mRNA 剪接。[4]、[5] 通过这种作用，pladienolide B 有效地阻止增殖细胞的生长，平均 IC50 值为 1.6 nM 对六种胃癌细胞系。[6],[7] 在使用人类癌细胞的小鼠体内产生的异种移植肿瘤中，pladienolide B 阻断 mRNA 剪接并诱导细胞凋亡，在治疗后两周内清除肿瘤。[7]
Reference:
[1]. Naro, C., and Sette, C. Phosphorylation-mediated regulation of alternative splicing in cancer. Int.J.Cell Biol. 2013, 1-16 (2013).
[2]. Webb, T.R., Joyner, A.S., and Potter, P.M. The development and application of small molecule modulators of SF3b as therapeutic agents for cancer. Drug Discovery Today 18(1-2), 43-49 (2013).
[4]. Yokoi, A., Kotake, Y., Takahashi, K., et al. Biological validation that SF3b is a target of the antitumor macrolide pladienolide. FEBS Journal 278(24), 4870-4880 (2011).
[5]. Kotake, Y., Sagane, K., Owa, T., et al. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nature Chemical Biology 3, 570-575 (2007).
[6]. Effenberger, K.A., Anderson, D.D., Bray, W.M., et al. Coherence between cellular responses and in vitro splicing inhibition for the anti-tumor drug pladienolide B and its analogs. The Journal of Biological Chemisty 289, 1938-1947 (2014).
[7]. Sato, M., Muguruma, N., Nakagawa, T., et al. High antitumor activity of pladienolide B and its derivative in gastric cancer. Cancer Science 105(1), 110-116 (2014).