Siddique Abu Bakar, Ayoub Nehad M, Tajmim Afsana, Meyer Sharon A, Hill Ronald A, El Sayed Khalid A
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
Cancers (Basel). 2019 May 8;11(5):637. doi: 10.3390/cancers11050637.
Breast cancer (BC) recurrence represents a challenge for survivors who have had their primary tumors surgically excised, and/or have completed radiation, neoadjuvant, or adjuvant therapeutic regimens. Current BC treatments mostly lack the ability to reduce the risk of disease recurrence. About 70% of BC patients will subsequently suffer disease relapse, manifesting as local, regional, or distant tumor recurrence, which clearly underscores the urgent need to discover novel recurrence inhibitors. (-)-Oleocanthal (OC) is a natural phenolic, found so far exclusively in extra-virgin olive oil (EVOO). OC exerts documented bioactivities against diverse cancer types, inflammation, and neurodegenerative diseases. Herein we report the novel activity of daily oral treatment with OC (10 mg/kg) in preventing BC locoregional recurrence in a nude mouse xenograft model generated by orthotopic inoculation with BT-474 cells as a luminal type B model. We further report inhibition of tumor recurrence by OC after completion of a lapatinib neoadjuvant regimen. However, in a recurrence model of triple-negative breast cancer (TNBC), OC treatment (10 mg/kg) did not effectively prevent tumor recurrence, but rather, was seen to significantly reduce the growth of recurrent tumors as compared to vehicle control-treated animals. Inhibition of tumor recurrence was associated with significant serum level reductions of the human BC recurrence marker CA 15-3 at the study end in animals treated with OC. OC treatment upregulated the expression of the epithelial marker E-cadherin and downregulated the levels of the mesenchymal marker vimentin in recurrent tumors vs. untreated control animals. OC treatment also reduced the activation of MET and HER2 receptors, as indicated by reduced phosphorylation levels of these proteins in recurrent tumors vs. controls. Collectively, the results of our studies provide the first evidence for suppression of BC tumor recurrence by oral OC treatment in an animal model for such recurrence, and furthermore, highlight favorable prospects for this natural product to emerge as a first-in-class BC recurrence inhibitor.
乳腺癌（BC）复发对于那些已通过手术切除原发性肿瘤和/或已完成放疗、新辅助或辅助治疗方案的幸存者来说是一项挑战。目前的BC治疗大多缺乏降低疾病复发风险的能力。约70%的BC患者随后会出现疾病复发，表现为局部、区域或远处肿瘤复发，这清楚地凸显了发现新型复发抑制剂的迫切需求。（-）-油橄榄苦素（OC）是一种天然酚类物质，迄今为止仅在特级初榨橄榄油（EVOO）中发现。OC已被证明对多种癌症类型、炎症和神经退行性疾病具有生物活性。在此，我们报告了在以BT-474细胞原位接种建立的裸鼠异种移植模型（作为腔面B型模型）中，每日口服OC（10 mg/kg）预防BC局部区域复发的新活性。我们还报告了在拉帕替尼新辅助治疗方案完成后，OC对肿瘤复发的抑制作用。然而，在三阴性乳腺癌（TNBC）的复发模型中，OC治疗（10 mg/kg）并不能有效预防肿瘤复发，相反，与载体对照处理的动物相比，OC治疗可显著降低复发肿瘤的生长。在研究结束时，用OC处理的动物血清中人类BC复发标志物CA 15-3的水平显著降低，这与肿瘤复发的抑制相关。与未处理的对照动物相比，OC治疗上调了复发肿瘤中上皮标志物E-钙黏蛋白的表达，并下调了间充质标志物波形蛋白的水平。OC治疗还降低了MET和HER2受体的激活，这表现为复发肿瘤中这些蛋白的磷酸化水平低于对照。总体而言，我们的研究结果首次证明了在动物复发模型中口服OC治疗可抑制BC肿瘤复发，此外，还突出了这种天然产物成为一流BC复发抑制剂的良好前景。
