Yates Travis J, Lopez Luis E, Lokeshwar Soum D, Ortiz Nicolas, Kallifatidis Georgios, Jordan Andre, Hoye Kelly, Altman Norman, Lokeshwar Vinata B
Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
J Natl Cancer Inst. 2015 Apr 13;107(7). doi: 10.1093/jnci/djv085. Print 2015 Jul.
Prevention and treatment of advanced prostate cancer (PCa) by a nontoxic agent can improve outcome, while maintaining quality of life. 4-methylumbelliferone (4-MU) is a dietary supplement that inhibits hyaluronic acid (HA) synthesis. We evaluated the chemopreventive and therapeutic efficacy and mechanism of action of 4-MU.
TRAMP mice (7-28 per group) were gavaged with 4-MU (450mg/kg/day) in a stage-specific treatment design (8-28, 12-28, 22-28 weeks). Efficacy of 4-MU (200-450mg/kg/day) was also evaluated in the PC3-ML/Luc(+) intracardiac injection and DU145 subcutaneous models. PCa cells and tissues were analyzed for HA and Phosphoinositide 3-kinase (PI-3K)/Akt signaling and apoptosis effectors. HA add-back and myristoylated Akt (mAkt) overexpression studies evaluated the mechanism of action of 4-MU. Data were analyzed with one-way analysis of variance and unpaired t test or Tukey's multiple comparison test. All statistical tests were two-sided.
While vehicle-treated transgenic adenocarcinoma of the prostate (TRAMP) mice developed prostate tumors and metastases at 28 weeks, both were abrogated in treatment groups, without serum/organ toxicity or weight loss; no tumors developed at one year, even after stopping the treatment at 28 weeks. 4-MU did not alter the transgene or neuroendocrine marker expression but downregulated HA levels. However, 4-MU decreased microvessel density and proliferative index (P < .0001,). 4-MU completely prevented/inhibited skeletal metastasis in the PC3-ML/Luc(+) model and DU145-tumor growth (85-90% inhibition, P = .002). 4-MU also statistically significantly downregulated HA receptors, PI-3K/CD44 complex and activity, Akt signaling, and β-catenin levels/activation, but upregulated GSK-3 function, E-cadherin, and apoptosis effectors (P < .001); HA addition or mAkt overexpression rescued these effects.
4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that targets PCa development, growth, and metastasis by abrogating HA signaling.
使用无毒药物预防和治疗晚期前列腺癌（PCa）可改善预后，同时维持生活质量。4-甲基伞形酮（4-MU）是一种膳食补充剂，可抑制透明质酸（HA）的合成。我们评估了4-MU的化学预防和治疗效果及其作用机制。
采用阶段特异性治疗设计（8 - 28周、12 - 28周、22 - 28周），对TRAMP小鼠（每组7 - 28只）灌胃给予4-MU（450mg/kg/天）。还在PC3-ML/Luc(+)心内注射和DU145皮下模型中评估了4-MU（200 - 450mg/kg/天）的疗效。对前列腺癌细胞和组织进行HA、磷酸肌醇3激酶（PI-3K）/Akt信号传导及凋亡效应因子分析。HA回补和肉豆蔻酰化Akt（mAkt）过表达研究评估了4-MU的作用机制。数据采用单因素方差分析、非配对t检验或Tukey多重比较检验进行分析。所有统计检验均为双侧检验。
未处理的前列腺转基因腺癌（TRAMP）小鼠在28周时出现前列腺肿瘤和转移，而治疗组的肿瘤和转移均被消除，且无血清/器官毒性或体重减轻；即使在28周时停止治疗，1年后也未出现肿瘤。4-MU未改变转基因或神经内分泌标志物的表达，但下调了HA水平。然而，4-MU降低了微血管密度和增殖指数（P <.0001）。4-MU在PC3-ML/Luc(+)模型中完全预防/抑制了骨转移，在DU145模型中抑制了肿瘤生长（85 - 90%抑制，P =.002）。4-MU在统计学上还显著下调了HA受体、PI-3K/CD44复合物及活性、Akt信号传导和β-连环蛋白水平/激活，但上调了GSK-3功能、E-钙黏蛋白和凋亡效应因子（P <.001）；添加HA或过表达mAkt可挽救这些效应。
4-MU是一种有效的无毒口服化学预防和治疗药物，通过消除HA信号传导靶向前列腺癌的发生、生长和转移。
