Chemosensitizing properties of ß-caryophyllene oxide in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive malignant tumor, often associated with multidrug resistance, which limits the efficacy of conventional anticancer drugs [1]. In the last years, the possibility to affect tumour growth with multi-target therapies acting in synergy or on different targets has been highlighted. This approach enables to increase low-dose anticancer drug efficacy and limit systemic toxicity. In present study, the ability of the natural sesquiterpene ß-caryophyllene oxide (CRYO) to enhance the response of HCC to the first-line drug sorafenib (SOR) has been investigated. The cytotoxicity of CRYO alone or in combination with SOR was evaluated by MTT assay in different HCC cells [2,3]. Moreover, its ability to modulate both activity and expression of Pgp, MRP1/2 and STAT3 was measured2,3. At last, the sorafenib chemosensitization by the natural sesquiterpene was assessed in a liver xenograft model [2]. Despite a low cytotoxicity in our cellular models, CRYO was able to synergistically increase HCC cell sensitivity to SOR. CRYO also inhibited Pgp and MRP1/2 activity and reduced the SOR-induced expression of Pgp, MRP1/2 and STAT3 (Ser 727). In vivo experiments highlighted the combination of CRYO and SOR was able to inhibit the tumor growth of about 58%, despite a null effect of the anticancer drug alone. In conclusion, our results highlight the possible role of CRYO as a chemosensitizing agent in combination with SOR and support its potential usefulness to reverse the sorafenib-induced multidrug resistance by targeting Pgp and MRP1/2 transporters, and/or the STAT3 pathway. References [1] Fouquet et al., Oncotarget 2016, 7(22):32493. [2] Di Giacomo et al., Arch Toxicol;93(3):623-634. [3] Di Sotto et al., Int J Mol Sci. 2020;21(2):633