Ovarian cancer (OC) is a "silent killer" with an annual incidence of 11.2 per 100,000 and mortality of 7.6 per 100,000. Most cases are diagnosed at advanced stages due to the lack of effective screening. Standard treatments—surgery and chemoradiotherapy—are limited by drug resistance, particularly to platinum agents, leading to recurrence and poor prognosis. Natural products like resveratrol (RVT), a polyphenol found in grapes and peanuts, offer potential as safe, multi-targeted adjunctive therapies. This review examines RVT's molecular interactions with OC-related proteins, its therapeutic mechanisms, and novel delivery systems.
Structural Properties and Protein Binding
RVT (3,4',5-trihydroxy-trans-stilbene) exists in trans and cis isomers, with trans-RVT being more potent. Its phenolic hydroxyl groups enable specific interactions with target proteins through hydrogen bonds, hydrophobic interactions, and π-π stacking. Molecular docking studies (AutoDock Vina) identified strong binding affinities with four key OC-associated proteins (Table 1, Fig. 2):
SIRT1 (PDB:5BTR, -8.3 kcal/mol): RVT stimulates SIRT1, an NAD+-dependent deacetylase overexpressed in OC, through hydrogen bonds with Asp298 and Lys444, potentially improving survival.
PLA2 (PDB:4QER, -6.9 kcal/mol): RVT inhibits this phospholipase involved in inflammation and lipid metabolism via hydrophobic interactions with Ile19/Phe5, reducing OC progression.
Estrogen Receptor α (E2, PDB:4PP6, -7.8 kcal/mol): RVT acts as a selective modulator, binding through π-π stacking with Phe404 and hydrogen bonds with Glu353/Leu387, affecting proliferation.
PPAR-γ (PDB:4JAZ, -8.0 kcal/mol): RVT activates this transcription factor via hydrophobic interactions with Phe264/Ile281, inducing G1 phase arrest.
Therapeutic Mechanisms in OC
Anti-inflammatory: RVT reduces inflammatory mediators (IL-6, PGE2, TNF-α) by inhibiting NF-κB activation and LPS-stimulated pathways. It downregulates COX-2 and iNOS expression in a dose-dependent manner.
Antioxidant: RVT scavenges ROS and enhances endogenous antioxidants. It protects against cisplatin-induced ovarian toxicity while selectively killing OC stem cells through ROS upregulation.
Antiproliferation and Cell Cycle Arrest: RVT inhibits cyclin D1 expression via AKT/GSK-3β and ERK1/2 pathways, causing G1 phase accumulation. It also blocks COX-2 activity and induces p53-dependent apoptosis (Fig. 3).
Autophagy Regulation: RVT modulates autophagy through Beclin-1 upregulation and LC3 cleavage. It enhances cisplatin sensitivity by inhibiting the Hh pathway and restoring autophagy-mediated apoptosis in drug-resistant cells (Fig. 4).
Novel Delivery Systems
Poor bioavailability limits RVT's clinical use. Innovative formulations improve delivery (Tables 2-3):
Nanoparticles: RVT-ZnO, RVT-bovine serum albumin, and RVT-human serum albumin nanoparticles enhance cellular uptake, ROS-mediated apoptosis, and tumor targeting.
Co-delivery systems: Polymeric micelles co-loading RVT with curcumin or quercetin reduce doxorubicin cardiotoxicity and improve OC cell killing.
Theranostic platforms: RVT-gold nanoparticles enable multimodal imaging (fluorescence/CT) while delivering therapy. RVT liposomes with MRI guidance show promise for targeted treatment.
Chemo- and Radiosensitization
RVT reverses multidrug resistance by inhibiting P-glycoprotein and MDR1 gene expression. It synergizes with platinum drugs (3.1-fold increased cisplatin cytotoxicity) by downregulating NF-κB. As a radioprotectant, RVT reduces radiation-induced chromosomal aberrations, restores salivary function, and enhances tumor cell radiosensitivity through REG III pathway activation and prolonged G2/M arrest.
Clinical Evidence
While no direct OC clinical trials exist, RVT shows benefits in ovarian metabolic disorders (Table 4):
PCOS: Reduced fasting glucose, insulin levels, and hair loss; improved menstrual regularity.
Ovarian insufficiency: Enhanced endocrine function and quality of life.
Future Perspectives
RVT's multi-targeted action offers a strategy to overcome chemotherapy resistance. Key priorities include:
Standardized pharmacokinetic studies and formulation development.
Large-scale clinical trials to establish efficacy in OC.
Integration with advanced imaging (MRI) for real-time treatment monitoring.
Mechanistic studies using network pharmacology to elucidate complex pathways.
Conclusions
RVT demonstrates significant therapeutic potential in OC through multi-target protein interactions, anti-inflammatory/antioxidant effects, cell cycle regulation, autophagy modulation, and chemosensitization. Novel nanoformulations address bioavailability challenges, while its radiosensitizing properties enhance radiotherapy. Despite strong preclinical evidence, translation to clinical practice requires rigorous pharmacokinetic evaluation, standardized formulations, and well-designed trials. RVT's ability to target multiple pathways simultaneously positions it as a promising adjunctive therapy to overcome drug resistance and improve outcomes in ovarian cancer.
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The study was recently published in the Future Integrative Medicine .
Future Integrative Medicine (FIM) is the official scientific journal of the Capital Medical University. It is a prominent new journal that promotes future innovation in medicine.It publishes both basic and clinical research, including but not limited to randomized controlled trials, intervention studies, cohort studies, observational studies, qualitative and mixed method studies, animal studies, and systematic reviews.
