Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment

Background: Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential. Purpose: The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA. Methods: Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-kappa B and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities. Conclusion: BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound.