Additive antiangiogenesis effect of ginsenoside Rg3 with low-dose metronomic temozolomide on rat glioma cells both in vivo and in vitro

Background: Glioblastoma is the most common and deadly primary brain tumor in adults. Low-dose, metronomic (LDM) temozolomide (TMZ) displays improved efficacy in the treatment of glioblastoma by targeting angiogenesis, but has a limited effect on recurrence. The antiangiogenesis drug ginsenoside Rg3 (RG3) is the main active ingredient of ginseng, a popular herbal medicine. Methods: Using an in vitro and a rat model of an orthotopic glioma allograft, this study was to determine whether RG3 enhanced the antiangiogenesis activity of LDM TMZ in the treatment of glioblastoma. Results: Our results showed that combined use of TMZ with RG3 displayed additive inhibition on proliferation of both human umbilical vein endothelial cells (HUVEC) and rat C6 glioma cells in vitro. They additively arrested cell cycle, increased apoptosis, and decreased VEGF-A and BCL-2 expression in HUVEC. Antiangiogenesis effect was also evaluated in the rat model of orthotopic glioma allograft, based upon markers including relative cerebral blood volume (rCBV) by magnetic resonance imaging (MRI), VEGF levels and microvessel density (MVD)/CD34 staining. LDM TMZ alone was potent in suppressing angiogenesis and tumor growth, whereas RG3 alone only had modest antiangiogenesis effects. Combined treatment significantly and additively suppressed angiogenesis, without additive inhibitory effects on allografted tumor growth. Conclusions: These data provide evidence showing the efficacy of LDM TMZ on glioma treatment. The combined additive antiangiogenesis effect suggests that RG3 has the potential to further increase the efficacy of LDM TMZ in the treatment of glioblastoma.