Hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and ductal adenocarcinoma (PDAC) are among the major malignancies occurring in the hepato-biliary-pancreatic system. They share a common origin along with high aggressiveness, chemoresistance and poor prognosis. Chemoresistance is due to many cell alterations, including metabolic changes, aberrant signalings for cell survival and growth and overexpression of efflux pumps. Despite the advances in the pathogenesis of HCC, PDAC and CCA, current chemotherapy regimens produce very limited survival benefits and severe side effects. To overcome these drawbacks, a combination therapy between anticancer drug and chemosensitizing agent, able to potentiate low dose drug efficacy, has been approached. Besides the reduction of anticancer drug toxicity, it allows the simultaneous blockage of distinct key molecules in oncogenic signalling, thus affecting both cancer cell proliferation and activation of chemoresistance. In this context, present project aims at evaluating the chemosensitizing properties of caryophyllane sesquiterpenes in HCC, CCA and PDAC cells, focusing on the modulation of HIF-1alpha/STAT3/Nrf2 axis to control metabolic reprogramming, cell survival and growth, and ABC transporter function and expression. At last, tolerability of the treatments in normal cells, which is an important goal to overcome the toxicity drawback of standard chemotherapy, will be evaluated. The expected results will be useful to better understand the mechanism of drug resistance in these cancers and to develop more effective future treatment strategies. Also, a possible further interest in caryophyllane sesquiterpenes as chemosensitizing and chemopreventive agents will be achieved. The project will be developed in vitro, using suitable human cancer and noncancerous cell lines. Feasibility of this project is assured by the availability of adequate laboratory infrastructures and instrumentation for cell analysis.
