We studied the mechanism of the cytotoxic activity of
BZL101, an aqueous extract from the herb Scutellaria barbata D. Don, which is currently in phase II clinical trial in patients with advanced
breast cancer. The phase I trial showed favorable toxicity profile and promising efficacy. We report here that
BZL101 induces cell death in
breast cancer cells but not in non-transformed mammary epithelial cells. This selective cytotoxicity is based on strong induction by
BZL101 of
reactive oxygen species (ROS) in
tumor cells. As a consequence,
BZL101 treated
cancer cells develop extensive oxidative DNA damage and succumb to necrotic death. Data from the expression profiling of cells treated with
BZL101 are strongly supportive of a death pathway that involves oxidative stress, DNA damage and activation of death-promoting genes. In
breast cancer cells oxidative damage induced by
BZL101 leads to the hyperactivation of
poly (ADP-ribose) polymerase (PARP), followed by a sustained decrease in levels of
NAD and depletion of
ATP, neither of which are observed in non-transformed cells. The hyperactivation of PARP is instrumental in the necrotic death program induced by
BZL101, because inhibition of PARP results in suppression of
necrosis and activation of the apoptotic death program.
BZL101 treatment leads to the inhibition of glycolysis selectively in
tumor cells, evident from the decrease in the enzymatic activities within the glycolytic pathway and the inhibition of
lactate production. Because
tumor cells frequently rely on glycolysis for energy production, the observed inhibition of glycolysis is likely a key factor in the energetic collapse and necrotic death that occurs selectively in
breast cancer cells. The promising selectivity of
BZL101 towards
cancer cells is based on metabolic differences between highly glycolytic
tumor cells and normal cells.