Herbal medicines and their bioactive compounds are increasingly being recognized as useful drugs for
cancer treatments. The parasitic fungus Cordyceps militaris is an attractive anticancer herbal since it shows very powerful anticancer activity due to its phytocompound
cordycepin. We previously discovered and reported that a high amount of
xylitol is present in Cordyceps militaris extract, and that
xylitol unexpectedly showed anticancer activity in a
cancer-selective manner. We thus hypothesized that
xylitol could become a useful supplement to help prevent various
cancers, if we can clarify the specific machinery by which
xylitol induces
cancer cell death. It is also unclear whether
xylitol acts on
cancer suppression in vivo as well as in vitro. Here we show for the first time that induction of the
glutathione-degrading
enzyme CHAC1 is the main cause of
xylitol-induced apoptotic cell death in
cancer cells. The induction of CHAC1 is required for the endoplasmic reticulum (ER) stress that is triggered by
xylitol in
cancer cells, and is linked to a second induction of oxidative stress in the treated cells, and eventually leads to apoptotic cell death. Our in vivo approach also demonstrated that an
intravenous injection of
xylitol had a
tumor-suppressing effect in mice, to which the
xylitol-triggered ER stress also greatly contributed. We also observed that
xylitol efficiently sensitized
cancer cells to chemotherapeutic drugs. Based on our findings, a chemotherapeutic strategy combined with
xylitol might improve the outcomes of patients facing
cancer.