Knobloch Thomas J, Uhrig Lana K, Pearl Dennis K, Casto Bruce C, Warner Blake M, Clinton Steven K, Sardo-Molmenti Christine L, Ferguson Jeanette M, Daly Brett T, Riedl Kenneth, Schwartz Steven J, Vodovotz Yael, Buchta Anthony J, Schuller David E, Ozer Enver, Agrawal Amit, Weghorst Christopher M
The Ohio State University, Columbus, Ohio. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.
The Ohio State University, Columbus, Ohio. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. Department of Statistics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio.
Cancer Prev Res (Phila). 2016 Feb;9(2):159-71. doi: 10.1158/1940-6207.CAPR-15-0187. Epub 2015 Dec 23.
Black raspberries (BRB) demonstrate potent inhibition of aerodigestive tract carcinogenesis in animal models. However, translational clinical trials evaluating the ability of BRB phytochemicals to impact molecular biomarkers in the oral mucosa remain limited. The present phase 0 study addresses a fundamental question for oral cancer food-based prevention: Do BRB phytochemicals successfully reach the targeted oral tissues and reduce proinflammatory and antiapoptotic gene expression profiles? Patients with biopsy-confirmed oral squamous cell carcinomas (OSCC) administered oral troches containing freeze-dried BRB powder from the time of enrollment to the date of curative intent surgery (13.9 ± 1.27 days). Transcriptional biomarkers were evaluated in patient-matched OSCCs and noninvolved high at-risk mucosa (HARM) for BRB-associated changes. Significant expression differences between baseline OSCC and HARM tissues were confirmed using a panel of genes commonly deregulated during oral carcinogenesis. Following BRB troche administration, the expression of prosurvival genes (AURKA, BIRC5, EGFR) and proinflammatory genes (NFKB1, PTGS2) were significantly reduced. There were no BRB-associated grade 3-4 toxicities or adverse events, and 79.2% (N = 30) of patients successfully completed the study with high levels of compliance (97.2%). The BRB phytochemicals cyanidin-3-rutinoside and cyanidin-3-xylosylrutinoside were detected in all OSCC tissues analyzed, demonstrating that bioactive components were successfully reaching targeted OSCC tissues. We confirmed that hallmark antiapoptotic and proinflammatory molecular biomarkers were overexpressed in OSCCs and that their gene expression was significantly reduced following BRB troche administration. As these molecular biomarkers are fundamental to oral carcinogenesis and are modifiable, they may represent emerging biomarkers of molecular efficacy for BRB-mediated oral cancer chemoprevention.
黑树莓（BRB）在动物模型中对呼吸道消化道癌症发生具有强大的抑制作用。然而，评估BRB植物化学物质影响口腔黏膜分子生物标志物能力的转化临床试验仍然有限。本0期研究解决了口腔癌食物预防的一个基本问题：BRB植物化学物质能否成功到达目标口腔组织并降低促炎和抗凋亡基因表达谱？活检确诊为口腔鳞状细胞癌（OSCC）的患者从入组到根治性手术日期（13.9±1.27天）服用含冻干BRB粉末的口服含片。在患者匹配的OSCC和未受累的高危黏膜（HARM）中评估转录生物标志物与BRB相关的变化。使用一组在口腔癌发生过程中通常失调的基因确认了基线OSCC和HARM组织之间的显著表达差异。服用BRB含片后，存活基因（AURKA、BIRC5、EGFR）和促炎基因（NFKB1、PTGS2）的表达显著降低。没有与BRB相关的3-4级毒性或不良事件，79.2%（N=30）的患者以高依从性（97.2%）成功完成了研究。在所有分析的OSCC组织中均检测到BRB植物化学物质矢车菊素-3-芸香糖苷和矢车菊素-3-木糖基芸香糖苷，表明生物活性成分成功到达目标OSCC组织。我们证实，标志性的抗凋亡和促炎分子生物标志物在OSCC中过表达，并且在服用BRB含片后其基因表达显著降低。由于这些分子生物标志物是口腔癌发生的基础且可被调节，它们可能代表BRB介导的口腔癌化学预防分子疗效的新兴生物标志物。
