Ricerc@Sapienza

Biliary tract cancers are heterogeneous and aggressive tumors usually classified into cholangiocarcinoma (both intrahepatic and extrahepatic) and gallbladder cancer, which display different phenotypic characteristics. Early phases are frequently asymptomatic, so many patients are diagnosed at advanced stages, when therapies are less effectives. Gemcitabine plus cisplatin is the reference regimen for systemic chemotherapy, although other drugs are commonly used (i.e. doxorubicin, sorafenib and regorafenib). However, their success is rather low because of multidrug resistance (MDR) development. Different mechanisms can contribute to the occurrence of chemoresistance, although the over-expression of ATP-binding cassette (ABC) transporters, often mediated by STAT3 and Nrf2 pathways, seems to be mainly involved. These proteins actively pump several lipophilic molecules across cell biomembrane, thereby increasing drug efflux from cells. Therefore, using ABC-transporter inhibitors (namely chemosensitizers) in association with cytotoxic drugs represents an emerging approach to overcome MDR. In this context, in the present study the ability of two natural sesquiterpenes, ß-caryophyllene (CRY) and ß-caryophyllene oxide (CRYO), to act as chemosensitizers in cholangiocarcinoma and gallbladder cancer cells will be evaluated. Cytotoxicity of the test substances, alone or in combination with anticancer drugs, will be evaluated by MTT assay. Also, selected cell lines will be characterized for the ABC transporter, STAT3 and Nrf2 expression. The possible interference of CRY and CRYO with expression and function of ABC-transporters and STAT3/Nrf2 pathway will be studied by western blot analysis, as a potential chemosensitizing mechanism. The expected results will enable to characterize the possible usefulness of chemosensitizing caryophyllane sesquiterpenes in cholangiocarcinoma and gallbladder cells, thus suggesting a new strategy to support chemotherapy and overcome chemoresistance.