Glioblastoma, the most lethal
brain tumor, remains incurable despite aggressive
chemotherapy and surgical interventions. New chemotherapeutics for
glioblastoma have been explored in preclinical models and some agents have reached the clinical setting. However, success rates are not significant. Previous investigations involving
diallyl trisulfide (DATS), a garlic compound, indicated significant anti-
cancer effects in
glioblastoma in vitro. DATS has also been shown to inhibit
histone deacetylase activity and impede
glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG
tumor by multiple pro-apoptotic pathways via inhibiting
histone deacetylase (HDAC). To prove this, we developed ectopic U87MG
tumors in SCID mice and treated them daily with
intraperitoneal injections of DATS for 7 days. Results indicated that DATS (10 μg/kg-10 mg/kg) dose-dependently reduced
tumor mass and number of mitotic cells within
tumors. Histological and biochemical assays demonstrated that DATS reduced mitosis in
tumors, decreased HDAC activity, increased acetylation of H3 and H4, inhibited cell cycle progression, decreased pro-
tumor markers (e.g.,
survivin, Bcl-2, c-Myc, mTOR, EGFR,
VEGF), promoted apoptotic factors (e.g., bax, mcalpian, active
caspase-3), and induced DNA fragmentation. Our data also demonstrated an increase in p21Waf1 expression, which correlated with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and
enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. Collectively, our results clearly demonstrated that DATS could be an effective therapeutic agent in preventing
tumor progression and inducing apoptosis in human
glioblastoma in vivo, without impairing hepatic function.