Farnesol is a non-cyclic
sesquiterpene (
isoprenoid) found in the
essential oils of many plants. In
cancer biology, farnesylation of mutated Ras
oncoproteins allows the
proteins to dock to the membrane and be functionalized. Therefore,
farnesyltransferase is a target for
drug development to inhibit Ras.
Farnesol exhibits cytotoxic activity against
tumor cells in vitro and in vivo, implying that novel treatment strategies may be devised independent of Ras farnesylation.
Tumors frequently develop resistance towards standard
chemotherapies, and thus novel agents are urgently required that bypass the cross-resistance evoked by established anticancer drugs. We investigated whether classical mechanisms of drug resistance such as
ATP-binding cassette transporters (
P-glycoprotein/MDR1,
MRP1, BCRP), the tumor suppressor gene TP53, and the oncogene EGFR play a role in the response of
tumor cells to
farnesol. Remarkably, none of these genes conferred resistance to
farnesol, indicating that this compound may be useful for the treatment of otherwise
drug-resistant and refractory
tumors expressing these mechanisms of resistance. Furthermore, we applied a pharmacogenomic approach to explore molecular determinants of sensitivity and resistance to
farnesol. Among the candidates were genes involved in apoptosis (STAB2, NUMBL), regulation of transcription (CDYL, FOXA2) and diverse other functional groups (INE1, CTRL, MRS2, NEB, LMO7, C9orf3, EHBP1). The fact that these genes are not associated with resistance to traditional anticancer drugs suggests
farnesol may possess a novel mechanism of action, and consequently might bypass drug resistance to established chemotherapeutics.