Targets and pathways involved in the antitumor activity of citral and its stereo-isomers

This review provides a comprehensive analysis of the anticancer potential of the natural product citral (CIT) found in many plants and essential oils, and extensively used in the food and cosmetic industry. CIT is composed of two stereoisomers, the trans-isomer geranial being a more potent anticancer compound than the cis-isomer neral. CIT inhibits cancer cell proliferation and induces cancer cell apoptosis. Its pluri-factorial mechanism of anticancer activity is essentially based on three pillars: (i) a drug-induced accumulation of reactive oxygen species in cancer cells leading to an oxidative burst and DNA damages, (ii) a colchicine-like inhibition of tubulin polymerization and promotion of microtubule depolymerization, associated with an inhibition of the microtubule affinity-regulating kinase MARK4, and (iii) a potent inhibition of the aldehyde dehydrogenase isoform ALDH1A3 which is associated with cancer stem cell proliferation and chemoresistance. This unique combination of targets and pathways confers a significant anticancer potential. However, the intrinsic potency of CIT is limited, mainly because the drug is not very stable and has a low bioavailability and it does not present a high selectivity for cancer cells versus non-tumor cells. Stable formulations of CIT, using cyclodextrins, biodegradable polymers, or various nano-structured particles have been designed to enhance the bioavailability, to increase the effective doses window and to promote the anticancer activity. The lack of tumor cell selectivity is more problematic and limits the use of the drug in cancer therapy. Nevertheless, CIT offers interesting perspectives to design more potent analogues and drug combinations with a reinforced antitumor potential.