Bezielle (
BZL101) is a candidate oral
drug that has shown promising efficacy and excellent safety in the early phase clinical trials for advanced
breast cancer.
Bezielle is an aqueous extract from the herb Scutellaria barbata. We have reported previously that
Bezielle was selectively cytotoxic to
cancer cells while sparing non-transformed cells. In
tumor, but not in non-transformed cells,
Bezielle induced generation of ROS and severe DNA damage followed by hyperactivation of PARP, depletion of the cellular
ATP and
NAD, and inhibition of glycolysis. We show here that
tumor cells' mitochondria are the primary source of
reactive oxygen species induced by
Bezielle. Treatment with
Bezielle induces progressively higher levels of mitochondrial
superoxide as well as
peroxide-type ROS. Inhibition of mitochondrial respiration prevents generation of both types of ROS and protects cells from
Bezielle-induced death. In addition to glycolysis,
Bezielle inhibits oxidative phosphorylation in
tumor cells and depletes mitochondrial reserve capacity depriving cells of the ability to produce
ATP.
Tumor cells lacking functional mitochondria maintain glycolytic activity in presence of
Bezielle thus supporting the hypothesis that mitochondria are the primary target of
Bezielle. The metabolic effects of
Bezielle towards normal cells are not significant, in agreement with the low levels of oxidative damage that
Bezielle inflicts on them.
Bezielle is therefore a
drug that selectively targets
cancer cell mitochondria, and is distinguished from other such drugs by its ability to induce not only inhibition of OXPHOS but also of glycolysis. This study provides a better understanding of the mechanism of
Bezielle's cytotoxicity, and the basis of its selectivity towards
cancer cells.