Ahmed Nehal A, Siddique Abu Bakar, Tajmim Afsana, King Judy Ann, El Sayed Khalid A
Department of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
Foundational and Clinical Sciences Department, Thomas F. Frist, Jr. College of Medicine, Belmont University, 1900 Belmont Boulevard, Nashville, TN 37212, USA.
Molecules. 2025 Jul 28;30(15):3157. doi: 10.3390/molecules30153157.
Breast cancer (BC) is the most common malignancy and the second-leading cause of cancer-related mortalities in women. Epidemiological studies suggested the reduced BC incidence in Mediterranean populations due to the daily consumption of diets rich in extra-virgin olive oil (EVOO). EVOO secoiridoid phenolics are widely known for their positive outcomes on multiple cancers, including BC. The current study investigates the suppressive effects of individual and combined EVOO phenolics for BC progression and motility. Screening of a small library of EVOO phenolics at a single dose of 10 µM against the viability of the BC cell lines ZR-75-1 (luminal A) and MDA-MB-231 (triple negative BC, TNBC) identified oleocanthal (OC) and ligstroside aglycone (LA) as the most active hits. Screening of EVOO phenolics for BC cells migration inhibition identified OC, LA, and the EVOO lignans acetoxypinoresinol and pinoresinol as the most active hits. Combination studies of different olive phenolics showed that OC combined with LA had the best synergistic inhibitory effects against the TNBC MDA-MB-231 cells migration. A combination of 5 µM of each of OC and LA potently suppressed the migration and invasion of the MDA-MB-231 cells versus LA and OC individual therapies and vehicle control (VC). Animal studies using the ZR-75-1 BC cells orthotopic xenografting model in female nude mice showed significant tumor progression suppression by the combined OC-LA, 5 mg/kg each, ip, 3X/week treatments compared to individual LA and OC treatments and VC. The BC suppressive effects of the OC-LA combination were associated with the modulation of SMYD2-EZH2-STAT3 signaling pathway. A metastasis-clonogenicity animal study model using female nude mice subjected to tail vein injection of MDA-MB-231-Luc TNBC cells also revealed the effective synergy of the combined OC-LA, 5 mg/kg each, compared to their individual therapies and VC. Thus, EVOO cultivars rich in OC with optimal LA content can be useful nutraceuticals for invasive hormone-dependent BC and TNBC progression and metastasis.
乳腺癌（BC）是女性中最常见的恶性肿瘤，也是癌症相关死亡的第二大原因。流行病学研究表明，由于日常食用富含特级初榨橄榄油（EVOO）的饮食，地中海人群的乳腺癌发病率有所降低。EVOO中的裂环烯醚萜酚类化合物因其对包括乳腺癌在内的多种癌症具有积极作用而广为人知。本研究调查了单一和联合使用EVOO酚类化合物对乳腺癌进展和迁移的抑制作用。以10 µM的单剂量筛选一个小型EVOO酚类化合物库，检测其对乳腺癌细胞系ZR-75-1（腔面A型）和MDA-MB-231（三阴性乳腺癌，TNBC）活力的影响，结果确定油橄榄苦素（OC）和裂环烯醚苷元（LA）是活性最强的成分。筛选EVOO酚类化合物对乳腺癌细胞迁移的抑制作用，结果确定OC、LA以及EVOO木脂素乙酰氧基松脂醇和松脂醇是活性最强的成分。不同橄榄酚类化合物的联合研究表明，OC与LA联合使用对TNBC MDA-MB-231细胞迁移具有最佳的协同抑制作用。与单独使用LA和OC以及溶剂对照（VC）相比，5 µM的OC和LA联合使用能有效抑制MDA-MB-231细胞的迁移和侵袭。在雌性裸鼠中使用ZR-75-1乳腺癌细胞原位异种移植模型进行的动物研究表明，与单独使用LA和OC以及VC相比，每周腹腔注射3次、每次5 mg/kg的OC-LA联合治疗能显著抑制肿瘤进展。OC-LA联合治疗对乳腺癌的抑制作用与SMYD2-EZH2-STAT3信号通路的调节有关。在雌性裸鼠中使用尾静脉注射MDA-MB-231-Luc TNBC细胞建立的转移克隆形成动物研究模型也显示，与单独治疗和VC相比，5 mg/kg的OC-LA联合使用具有有效的协同作用。因此，富含OC且LA含量最佳的EVOO品种可能是用于侵袭性激素依赖性乳腺癌和TNBC进展及转移的有用营养保健品。
