caryophyllene-oxide and Liver-Neoplasms

Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes

Topics: Antibiotics, Antineoplastic; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Hepatocellular; Computer Simulation; Dose-Response Relationship, Drug; Doxorubicin; Humans; In Vitro Techniques; Liver Neoplasms; Polycyclic Sesquiterpenes; Sesquiterpenes; Tumor Cells, Cultured

Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as hepatocellular carcinoma (HCC). Here, we have investigated the ability of β-caryophyllene oxide (CRYO), a naturally occurring sesquiterpene component of many essential oils, to inhibit, at non-toxic doses, ABC pumps and improve the response of HCC cells to sorafenib. First, we have obtained a clonal subline (Alexander/R) derived from human hepatoma cells with enhanced multidrug resistance (MDR) associated to up-regulation (mRNA and protein) of MRP1 and MRP2. Analysis of fluorescent substrates export (flow cytometry) revealed that CRYO did not affect the efflux of fluorescein (MRP3, MRP4 and MRP5) but inhibited that of rhodamine 123 (MDR1) and calcein (MRP1 and MRP2). This ability was higher for CRYO than for other sesquiterpenes assayed. CRYO also inhibited sorafenib efflux, increased its intracellular accumulation (HPLC-MS/MS) and enhanced its cytotoxic response (MTT). For comparison, the effect of known ABC pumps inhibitors was also determined. They induced strong (diclofenac on MRPs), modest (verapamil on MDR1) or null (fumitremorgin C on BCRP) effect on sorafenib efflux and cytotoxicity. In the mouse xenograft model, the response to sorafenib treatment of subcutaneous tumors generated by mouse hepatoma Hepa 1-6/R cells, with marked MDR phenotype, was significantly enhanced by CRYO co-administration. In conclusion, at non-toxic dose, CRYO is able to chemosensitizating liver cancer cells to sorafenib by favoring its intracellular accumulation.

Topics: Animals; Antineoplastic Agents; ATP-Binding Cassette Transporters; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Mice; Neoplasm Proteins; Polycyclic Sesquiterpenes; Sorafenib