Jannati Shirin, Patel Adiba, Patnaik Rajashree, Banerjee Yajnavalka
Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai P.O. Box 505055, United Arab Emirates.
Birla Institute of Technology & Science, Pilani-Dubai Campus (BITS Pilani, Dubai Campus), Dubai International Academic City, Dubai P.O. Box 345055, United Arab Emirates.
Int J Mol Sci. 2025 Jun 9;26(12):5521. doi: 10.3390/ijms26125521.
Oleocanthal (OC), a secoiridoid phenolic compound exclusive to extra virgin olive oil (EVOO), has emerged as a promising nutraceutical with multifaceted anti-cancer properties. Despite its well-characterized anti-inflammatory and antioxidant effects, the mechanistic breadth and translational potential of OC in oncology remain underexplored and fragmented across the literature. This comprehensive review synthesizes and critically analyzes recent advances in the molecular, pharmacological, and translational landscape of OC's anti-cancer activities, providing an integrative framework to bridge preclinical evidence with future clinical application. We delineate the pleiotropic mechanisms by which OC modulates cancer hallmarks, including lysosomal membrane permeabilization (LMP)-mediated apoptosis, the inhibition of key oncogenic signaling pathways (c-MET/STAT3, PAR-2/TNF-α, COX-2/mPGES-1), the suppression of epithelial-to-mesenchymal transition (EMT), angiogenesis, and metabolic reprogramming. Furthermore, this review uniquely highlights the emerging role of OC in modulating drug resistance mechanisms by downregulating efflux transporters and sensitizing tumors to chemotherapy, targeted therapies, and immunotherapies. We also examine OC's bidirectional interaction with gut microbiota, underscoring its systemic immunometabolic effects. A major unmet need addressed by this review is the lack of consolidated knowledge regarding OC's pharmacokinetic limitations and drug-drug interaction potential in the context of polypharmacy in oncology. We provide an in-depth analysis of OC's poor bioavailability, extensive first-pass metabolism, and pharmacogenomic interactions, and systematically compile preclinical evidence on advanced delivery platforms-including nanocarriers, microneedle systems, and peptide-drug conjugates-designed to overcome these barriers. By critically evaluating the mechanistic, pharmacological, and translational dimensions of OC, this review advances the field beyond isolated mechanistic studies and offers a strategic blueprint for its integration into precision oncology. It also identifies key research gaps and outlines the future directions necessary to transition OC from a nutraceutical of dietary interest to a viable adjunctive therapeutic agent in cancer treatment.
油橄榄苦素（OC）是特级初榨橄榄油（EVOO）特有的一种裂环环烯醚萜类酚类化合物，已成为一种具有多方面抗癌特性的、有前景的营养保健品。尽管其抗炎和抗氧化作用已得到充分表征，但OC在肿瘤学中的作用机制广度和转化潜力在文献中仍未得到充分探索且较为零散。本综述全面综合并批判性地分析了OC抗癌活性在分子、药理和转化方面的最新进展，提供了一个综合框架，以将临床前证据与未来临床应用联系起来。我们阐述了OC调节癌症特征的多效性机制，包括溶酶体膜通透性（LMP）介导的细胞凋亡、关键致癌信号通路（c-MET/STAT3、PAR-2/TNF-α、COX-2/mPGES-1）的抑制、上皮-间质转化（EMT）、血管生成和代谢重编程的抑制。此外，本综述特别强调了OC在通过下调外排转运蛋白和使肿瘤对化疗、靶向治疗及免疫治疗敏感来调节耐药机制方面的新作用。我们还研究了OC与肠道微生物群的双向相互作用，强调了其全身免疫代谢效应。本综述解决的一个主要未满足需求是，在肿瘤学多药联合治疗背景下，关于OC的药代动力学局限性和药物-药物相互作用潜力缺乏综合知识。我们对OC的低生物利用度、广泛的首过代谢和药物基因组相互作用进行了深入分析，并系统汇编了关于先进递送平台的临床前证据，包括纳米载体、微针系统和肽-药物缀合物，这些平台旨在克服这些障碍。通过批判性地评估OC的作用机制、药理和转化维度，本综述推动该领域超越孤立的作用机制研究，并为将其整合到精准肿瘤学中提供了战略蓝图。它还确定了关键研究差距，并概述了将OC从一种具有饮食意义的营养保健品转变为癌症治疗中可行辅助治疗剂所需的未来方向。
