Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer

In recent years, interest in natural products such as alternative sources of pharmaceuticals for numerous chronic diseases, including tumors, has been renewed. Propolis, a natural product collected by honeybees, and polyphenolic/flavonoid propolis-related components modulate all steps of the cancer progression process. Anticancer activity of propolis and its compounds relies on various mechanisms: cell-cycle arrest and attenuation of cancer cells proliferation, reduction in the number of cancer stem cells, induction of apoptosis, modulation of oncogene signaling pathways, inhibition of matrix metalloproteinases, prevention of metastasis, anti-angiogenesis, anti-inflammatory effects accompanied by the modulation of the tumor microenvironment (by modifying macrophage activation and polarization), epigenetic regulation, antiviral and bactericidal activities, modulation of gut microbiota, and attenuation of chemotherapy-induced deleterious side effects. Ingredients from propolis also "sensitize" cancer cells to chemotherapeutic agents, likely by blocking the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B). In this review, we summarize the current knowledge related to the the effects of flavonoids and other polyphenolic compounds from propolis on tumor growth and metastasizing ability, and discuss possible molecular and cellular mechanisms involved in the modulation of inflammatory pathways and cellular processes that affect survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.