Figure 14.

Scheme of the possible network involved in the chemosensitizing and chemopreventive effects of β-caryophyllene towards doxorubicin in Mz-ChA-1 cholangiocarcinoma cells (A) and in H69 noncancerous cholangiocytes (B). Doxorubicin-induced oxidative stress, measured by the intracellular levels of reactive oxygen species (ROS), was partly reduced in combination with β-caryophyllene in Mz-ChA-1 cells, whereas GSH defenses, markedly upregulated by the sesquiterpene alone, were drastically reduced by both doxorubicin and its combination with β-caryophyllene, without affecting GSSG amount. Conversely, in H69 cholangiocytes, despite a GSH depletion similar to doxorubicin and not correlated with an increase in GSSG, the combined treatment of doxorubicin and β-caryophyllene enhanced ROS levels with respect to both control and the anticancer drug alone, despite a slight increase of GSH by the only β-caryophyllene. γH2AX, a biomarker of doxorubicin-induced DNA-damage, resulted partly lowered by the presence of β-caryophyllene in cholangiocarcinoma cells, with an almost complete inhibition in normal cholangiocytes. The increased G2/M checkpoint phase by β-caryophyllene could allow to repair the doxorubicin-damaged DNA in H69 cholangiocytes. In both cell lines, the phosphorylation of STAT3 at tyrosine 705 site, induced by the anticancer drug, resulted markedly lowered by the natural sesquiterpene. These networking effects result in an increased apoptotic fate in cholangiocarcinoma Mz-ChA-1 cells, despite an inhibition apoptosis in H69 noncancerous cholangiocytes.