Plicamycin（光辉霉素，AbMole，M9262）是一种从链霉菌（Streptomyces plicatus）发酵液中分离的抗肿瘤抗生素，属于蒽环类糖苷化合物家族，其分子结构包含一个蒽醌发色团和两个寡糖侧链，这种独特结构赋予其与DNA的小沟结合能力及对特定转录因子的选择性抑制作用^[1]。Plicamycin（CAS No.：18378-89-7）的分子机制核心在于其作为Sp1（Specificity protein 1）转录因子的抑制剂，Sp1是含有锌指结构域的转录因子，可结合GC富集启动子元件，调控大量管家基因和肿瘤相关基因的表达。Plicamycin（Mithramycin A，AbMole，M9262）通过与DNA的GC富集区域竞争性结合，阻断Sp1及其家族成员（Sp3、Sp4）与靶基因启动子的相互作用，从而抑制下游基因转录^[1]。

Plicamycin（CAS No.：18378-89-7）对Sp1靶基因的抑制效应具有广泛的生物学影响。在肿瘤研究中，多种癌基因和生长因子受体基因的启动子含有功能性Sp1结合位点，包括c-Myc、VEGF、TGF-β1、EGFR、HER2和胰岛素样生长因子受体（IGF-1R）。在前列腺癌细胞（LNCaP、PC-3、DU145）中，100 ~ 200 nM Plicamycin处理24–48小时可显著降低AR（雄激素受体）和PSA（前列腺特异性抗原）的mRNA及蛋白表达，抑制细胞增殖并诱导G1期阻滞^[2]。50 ~ 150 nM 的Plicamycin在肝细胞癌细胞（HepG2、Huh7）中，能抑制VEGF和HIF-1α的表达，降低血管生成能力，同时上调E-cadherin和下调N-cadherin及vimentin，提示其可抑制上皮-间质转化（EMT）进程^[3]。值得注意的是，Plicamycin（光辉霉素，AbMole，M9262）对正常细胞的影响相对较低：在前列腺上皮细胞（PrEC）中，500 nM以下浓度对细胞增殖和存活无明显影响，这可能与肿瘤细胞中存在更高的水平的Sp1有关^[2]。

Plicamycin（光辉霉素，AbMole，M9262）在动物神经退行疾病研究中也有应用。动物亨廷顿病（HD）是一种由亨廷顿蛋白（Htt）基因CAG重复扩增引起的神经退行性疾病，突变Htt的表达受Sp1调控。在HD细胞模型（突变Htt表达的ST14A细胞）中，100–200 nM Plicamycin可降低突变Htt的mRNA和蛋白水平，减少Htt聚集体形成，并改善线粒体功能；在HD R6/2转基因小鼠模型中，腹腔注射Plicamycin（0.5 mg/kg，隔日一次，从4周龄开始）可延迟运动症状出现、改善旋转棒表现，并延长生存期约15%^[4]。机制研究表明，Plicamycin（光辉霉素）通过抑制Sp1与突变Htt启动子的结合，降低突变Htt的转录，同时减少Sp1介导的兴奋性毒性基因（如NMDA受体亚基NR1）的表达，发挥多靶点神经保护作用^[4]。在脊髓延髓肌萎缩症（SBMA/Kennedy病）模型中，Plicamycin同样显示出降低雄激素受体（AR） polyQ 突变蛋白表达和改善运动功能的潜力^[5]。

参考文献及鸣谢

[1] Blume, S. W.; Snyder, R. C.; Ray, R.; et al. Mithramycin inhibits SP1 binding and selectively inhibits cellular and viral gene expression in GC-rich DNA. Biochemistry 1991, 30 (17), 4195–4202.

[2] Epping, M. T.; Wang, L.; Edel, M. J.; et al. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor pathway. Cell 2005, 122 (6), 835–847.

[3] Choi, J. H.; Kim, G. N.; Lim, J. W.; et al. Mithramycin A inhibits DNA binding of NF-κB and reduces interleukin-8 gene expression in TNF-α-stimulated and Helicobacter pylori-infected gastric epithelial cells. FEBS Letters 2006, 580 (17), 4101–4107.

[4] Ferrante, R. J.; Kubilus, J. K.; Lee, J.; et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. Journal of Neuroscience 2003, 23 (28), 9418–9427.

[5] Sopher, B. L.; Ladd, G. D.; Pineda, V. V.; et al. Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 2004, 41 (5), 687–699.

细胞实验参考

细胞系：HEp-2 cells  and KB cells（human cervical cancer cell lines with different genetic backgrounds）

方法：HEp-2 cells were cultured in DMEM containing 100 U/mL each of penicillin and streptomycin and 10% FBS; KB cells were cultured in DMEM containing 100 U/mL each of penicillin and streptomycin and 5% FBS in a humidified atmosphere containing 5% CO₂ at 37°C. Equal numbers of cells were seeded and allowed to attach. At 50–60% confluence, cells were treated with DMSO or indicated concentrations of Mith diluted in DMEM with 5% FBS for HEp-2 cells and 2.5% for KB cells. Mith was dissolved in 0.1% DMSO. Cell viability was determined.

浓度：20, 50, 100, 200 nM (HEp-2 cells); 20, 40, 80 nM (KB cells); IC50 values not explicitly stated in the extracted text but dose-dependent inhibition was observed

处理时间：48 h

参考文献：Scientific Reports (2014, 4: 7162)

* 上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。

动物实验参考

动物模型：Female nude mice; KB cells were suspended in sterile PBS and injected subcutaneously into the right flank of mice

配制：Mith was dissolved in 0.1% DMSO (for in vitro); for in vivo, Mith was diluted in PBS (vehicle) — the exact in vivo formulation is described as "treated with 0.2 mg/kg/day of Mith (i.p.)" with control mice receiving "an equal volume of vehicle" (PBS)

剂量：0.2 mg/kg/day

给药处理：Intraperitoneal (i.p.) injection, three times per week for 29 days

* 上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。  体内实验的工作液，建议现用现配，当天使用；如在配制过程中出现沉淀、析出现象，可以通过超声和（或）加热的方式助溶。  切勿一次性将产品全部溶解。

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