This comprehensive article explores the anti-cancer potential of stingless bee products such as honey, propolis, and geopropolis. Drawing on recent preclinical studies, it discusses their cytotoxic, pro-apoptotic, and anti-angiogenic effects on various cancer cell lines, highlights key bioactive compounds like cardol and mangiferonic acid, and outlines future research directions for clinical application.
Introduction
Stingless bees, belonging to the tribe Meliponini, are a diverse group of eusocial bees found mainly in tropical and subtropical regions. Unlike the well-known Apis mellifera (European honeybee), stingless bees produce a wider array of bioactive products such as honey, propolis, and geopropolis. These natural products have attracted increasing scientific interest for their medicinal properties, including anti-inflammatory, antimicrobial, antioxidant, and notably, anti-cancer effects.
Stingless bee products are rich in polyphenols, flavonoids, terpenes, phenolic acids, and other phytochemicals. These compounds are known to modulate oxidative stress, inflammation, cell proliferation, apoptosis, and angiogenesis—key biological processes involved in cancer development and progression.
Stingless Bee Products with Anticancer Properties
Propolis and Geopropolis
Propolis and geopropolis are resinous substances collected by bees from plant exudates and mixed with bee enzymes and wax. Propolis from stingless bees is chemically different from that of honeybees, with a broader diversity of bioactive compounds.
Studies have shown that propolis and geopropolis from various stingless bee species exhibit strong cytotoxic activity against multiple human cancer cell lines, including breast, colon, liver, cervical, lung, melanoma, and leukemia cells. This activity is largely attributed to phenolics and flavonoids that induce apoptosis, inhibit cell proliferation, and suppress tumor angiogenesis.
For instance, Trigona incisa propolis from Indonesia demonstrated potent cytotoxicity against liver (Hep-G2) and colon (SW620) cancer cells, with low IC₅₀ values (e.g., 0.71 μg/mL for Hep-G2). The key compound identified was a cardol isomer (5-pentadecyl resorcinol), which also triggered early apoptosis and G1-phase cell cycle arrest.
Propolis from Homotrigona fimbriata contained mangiferonic acid, which showed moderate anti-cancer effects against breast (MCF-7), cervical (HeLa), and colon (Caco-2) cancer cells, suggesting potential for further compound refinement and drug development.
Ethanolic extracts of Indian stingless bee propolis induced dose- and time-dependent cytotoxicity in several cancer cell lines such as MCF-7 (breast), HT-29 and Caco-2 (colon), and murine melanoma (B16F1). Apoptotic features such as nuclear fragmentation and chromatin condensation were observed within 24 hours of exposure.
Similarly, Melipona scutellaris geopropolis has demonstrated selective cytotoxicity, targeting cancer cells while sparing normal cells. This selectivity is critical in the development of cancer therapies that minimize side effects.
Stingless Bee Honey
Stingless bee honey differs from conventional honey not only in taste and texture but also in its chemical composition. It contains a higher proportion of phenolic acids, flavonoids, and organic acids, contributing to its potent antioxidant and anticancer effects.
In a study using Heterotrigona itama honey, glioblastoma cells (U-87 MG) showed significant reductions in viability after exposure to honey concentrations of 5–10%. Features of apoptosis, such as chromatin condensation and nuclear fragmentation, were clearly observed, pointing toward a direct anti-tumor effect.
Stingless bee honey also exhibited anti-proliferative effects against bladder cancer (T24) cells. Concentrations above 25 ppm caused more than 50% reduction in cell viability over 72 hours. This effect was attributed to oxidative stress induction, mitochondrial dysfunction, and DNA damage, ultimately leading to programmed cell death.
Mechanisms of Anticancer Action
Induction of Apoptosis: One of the most consistent mechanisms observed in studies is the induction of apoptosis (programmed cell death). Active compounds such as cardol, mangiferonic acid, and mangostins disrupt mitochondrial membrane potential, activate caspases, and cause DNA fragmentation in cancer cells.
Cell-Cycle Arrest: Certain compounds in stingless bee propolis, like cardol, have been shown to cause G1-phase arrest, thereby halting the proliferation of cancer cells and preventing tumor growth.
Anti-Angiogenic Activity: Tumors require the formation of new blood vessels (angiogenesis) to sustain growth. Some stingless bee compounds—like α-mangostin from Thai stingless bee propolis—were found to inhibit endothelial tube formation in vitro, suggesting a suppression of angiogenesis through ERK1/2 and p38 MAPK pathways.
Selective Cytotoxicity: Importantly, several extracts from geopropolis and propolis demonstrate cytotoxicity that is selective toward cancerous cells while sparing healthy ones. This feature increases their therapeutic potential while minimizing toxicity risks.
Antioxidant and Anti-inflammatory Effects: Chronic inflammation and oxidative stress are closely linked to cancer progression. The high antioxidant capacity of stingless bee honey and propolis helps mitigate these factors by scavenging free radicals, modulating inflammatory cytokines, and regulating cellular redox balance.
Key Bioactive Compounds Identified
- Cardol (5-pentadecyl resorcinol) – from Trigona incisa, induces apoptosis and cell-cycle arrest
- Mangiferonic acid – from Homotrigona fimbriata, displays moderate cytotoxic activity
- α-Mangostin – shows antiangiogenic and antiproliferative properties
- Phenolic acids and flavonoids – widely distributed in propolis and honey; responsible for antioxidant and apoptotic effects
Many more compounds remain unidentified or insufficiently studied, presenting a vast area for future research and compound isolation.
Current Limitations and Future Perspectives
Despite encouraging preclinical data, the anti-cancer potential of stingless bee products remains largely untapped in clinical settings. Most studies have been conducted in vitro (test tubes) or in cell cultures, with limited animal studies and almost no human trials. There is a strong need for:
- In vivo studies to evaluate bioavailability, metabolism, and toxicity
- Clinical trials to assess efficacy and safety in human populations
- Standardization of bee products to ensure consistent potency and reproducibility
- Isolation of novel compounds through bioassay-guided fractionation and metabolomics
Additionally, factors such as bee species, local flora, extraction methods, and geographic origin significantly affect the composition and bioactivity of these products.
Conclusion
Stingless bee products—especially propolis, geopropolis, and honey—offer a promising frontier in natural anti-cancer therapeutics. Their rich composition of polyphenols, flavonoids, and unique bioactive compounds contributes to a multi-targeted approach against cancer: inducing apoptosis, halting proliferation, inhibiting angiogenesis, and minimizing damage to normal cells. While current evidence from cell-line studies is compelling, robust in vivo and clinical research is essential to fully realize their therapeutic potential.