ANTITUMOR EFFECTS OF LINALOOL AND 1,8-CINEOLE, TWO PLANT-DERIVED ISOPRENOIDS, IN HUMAN LIVER CANCER CELLS

STÄRKEL, PETER; RODENAK KLADNIEW B.; CRESPO R; CASTRO A; GARCÍA DE BRAVO M

San Carlos de Bariloche

Simposio; The Fourth South American Symposium in Signal Transduction and Molecular Medicine; 2018

SISTAM 2018 ? IUBMB focused meeting

Hepatocellular carcinoma (HCC) is the second cause of cancer-related deathworldwide. HCC is one of the few cancers whose incidence and mortality is rising, and the 5-years survival rate is only about 5%. In this context, new therapies targeting signaling pathways involved in HCC are needed. Linalool (LN) and 1,8-cineole (CN) are plant-derived isoprenoids with multiple pharmacological activities including anticancer effects, however, their mechanisms of action remain largely unknown. In previous works, we showed the antiproliferative activity of LN and CN on HepG2 hepatocarcinoma cells. Here, we studied the cellular and molecular mechanisms involved. Exposure of HepG2 cancer cells to LN and CN significantly induced G0/G1 through inhibition of Cdk4, Cdk-2 and/or cyclin A and induction of p27 and p21 proteins. LN was also able to induce apoptosis, characterized by mitochondrial membrane potential (MMP) loss, caspase-3 activation, PARP cleavage and DNA fragmentation. At lower concentrations, both compounds inhibited Ras and/or Akt activity whereas higher amounts of them triggered reactive oxygen species (ROS) production, Akt phosphorylation and MAPKs (ERK, JNK and p38) activation. ROS were, at least in part, responsible for the cytotoxic effects since antioxidants partially rescued cell growth. In fact, antioxidants also prevented LN induced JNK activation and MMP loss, both of them related to apoptosis induction, suggesting a direct role of ROS in LN-induced apoptosis. Specific ERK and Akt inhibitors increased the antitumor activity, pointing Akt and ERK activation as prosurvival mechanisms in response to isoprenoid treatments. These findings describe novel antiproliferative mechanisms of action of LN and CN in HCC cells and suggestthem as potential chemotherapeutic agents in HCC therapy, employed alone orcombined with other antitumor drugs.