Natural products are characterized by extreme structural diversity and thus they offer a unique source for the identification of novel anti-
tumor agents. Herein, we report that the herbal substance
acteoside being isolated by advanced
phytochemical methods from Lippia citriodora leaves showed enhanced cytotoxicity against metastatic
tumor cells; acted in synergy with various
cytotoxic agents and it sensitized chemoresistant
cancer cells.
Acteoside was not toxic in physiological cellular contexts, while it increased oxidative load, affected the activity of proteostatic modules and suppressed
matrix metalloproteinases in tumor cell lines. Intraperitoneal or oral (via
drinking water) administration of
acteoside in a
melanoma mouse model upregulated
antioxidant responses in the
tumors; yet, only intraperitoneal delivery suppressed
tumor growth and induced anti-
tumor-reactive immune responses. Mass-spectrometry identification/quantitation analyses revealed that intraperitoneal delivery of
acteoside resulted in significantly higher, vs.
oral administration, concentration of the compound in the plasma and
tumors of treated mice, suggesting that its in vivo anti-
tumor effect depends on the route of administration and the achieved concentration in the
tumor. Finally, molecular modeling studies and enzymatic activity assays showed that
acteoside inhibits
protein kinase C. Conclusively,
acteoside holds promise as a chemical scaffold for the development of novel anti-
tumor agents.