Oleocanthal as a Multifunctional Anti-Cancer Agent: Mechanistic Insights, Advanced Delivery Strategies, and Synergies for Precision Oncology

Abstract

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.

Keywords: Mediterranean diet; cancer metabolism; gut microbiome; lysosomal membrane permeabilization; nanoparticle drug delivery; oleocanthal; polyphenols; precision oncology.

Figure 1

Comparative 2D structures of key phenolic compounds in extra virgin olive oil (EVOO). Structures of oleocanthal, oleacein, oleuropein, and hydroxytyrosol are shown to highlight variations in core scaffolds and functional groups. Oleocanthal’s unique dialdehydic secoiridoid structure distinguishes it from the other phenolics and may underlie its distinct bioactivity.

Figure 2

Schematic representation of oleocanthal-induced lysosomal membrane permeabilization triggering lysosome-mediated cell death pathways. The schematic depicts OC-induced LMP as a key event in lysosome-mediated cell death. OC promotes LMP through the activation of acid sphingomyelinase (ASM) and lysosomal membrane destabilization (LM), leading to the release of cathepsins into the cytoplasm. This triggers two distinct cell death pathways: apoptosis and necrosis. In the apoptotic pathway, cathepsins activate the Bid-Bax signaling cascade, leading to mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and caspase activation, ultimately resulting in programmed cell death. Conversely, excessive lysosomal damage leads to necrosis, characterized by membrane rupture and cytoplasmic disintegration.

Figure 3

Schematic on HGF/C-Met signaling in mesenchymal cells, activating RAS-ERK, RAC1-JNK, PI3K-AKT, and STAT3 pathways to regulate cellular processes. The diagram depicts the HGF/C-Met signaling cascade in mesenchymal cells, highlighting its role in key cellular processes. Upon HGF (Hepatocyte Growth Factor) binding, the C-Met receptor undergoes autophosphorylation, recruiting adaptor proteins Grb2, Gab1, and Shc, which activate multiple downstream pathways. The RAS-RAF-MEK-ERK axis promotes proliferation and differentiation, while RAC1-JNK influences cytoskeletal remodeling and motility. The PI3K-AKT pathway regulates survival and metabolism through mTOR and NF-κB, and STAT3 modulates gene transcription. Collectively, these signaling events drive metastasis, proliferation, survival, invasion, motility, and morphogenesis. The schematic also suggests the potential OC-mediated inhibition of HGF/C-Met signaling, indicating a therapeutic avenue for disrupting oncogenes.

Figure 4

Schematic representation of IL-6/JAK/STAT3 signaling pathway and oleocanthal-mediated inhibition. This schematic represents the IL-6/JAK/STAT3 signaling pathway and highlights the inhibitory role of OC, a natural phenolic compound. The pathway begins with IL-6 binding to its receptor complex (GP-80 and GP-130), leading to the activation of JAK1/2 kinases. This activation phosphorylates STAT3, which then translocates to the nucleus to regulate gene expression. The downstream effects include the promotion of cancer cell progression (Cyclin D1), apoptosis resistance (Bcl-2), and invasion (MMP2).

Figure 5

Role of polyphenols in gut microbiota regulation and cancer prevention. This schematic illustrates the beneficial effects of polyphenols on gut microbiota homeostasis and their potential role in cancer prevention. Polyphenols, derived from dietary sources such as fruits and vegetables, undergo bioconversion in the gut, leading to enhanced gut homeostasis. The diagram highlights several key mechanisms through which polyphenols influence microbiota composition, metabolic activity, and gut barrier integrity, ultimately contributing to reduced inflammation, improved immune function, and cancer inhibition.