Lung cancer is a leading cause of
cancer mortality worldwide. Novel and nontoxic agents targeting angiogenesis and
tumor cell proliferation and survival are desirable for
lung cancer chemoprevention and treatment. Previously we have reported that
6-(1-oxobutyl)-5,8-dimethoxy-1,4-naphthoquinone (OXO) exhibits anti-
tumor activity against S-180
sarcoma in vitro and in vivo. Here we studied the anti-angiogenic and apoptogenic attributes of OXO in vitro and in vivo targeting
lung cancer. In human umbilical vein endothelial cells (HUVECs), we show that OXO more potently inhibited
VEGF-stimulated than basic bFGF-stimulated HUVEC proliferation and capillary differentiation. In
Lewis lung carcinoma (LLC) cells, OXO not only induces S-phase arrest and mitochondria/
caspase-9 pathway mediated apoptosis, but also effectively down-regulated the
hypoxia-induced expression of HIF-1alpha and
VEGF at
mRNA and
protein levels in LLC and decreased
VEGF secretion into
conditioned culture media. OXO significantly reduced in vivo functional angiogenesis in the mouse
Matrigel plug assay. Furthermore, OXO potently inhibited the growth of LLC cells inoculated on the flank of syngenic mice at dosages that did not affect their
body weight. The in vivo anti-
cancer effect was associated with decreased HIF-1alpha and
VEGF expression, decreased microvessel density as well as a reduction of
tumor cell proliferation and increased
tumor cell apoptosis. Taken together, these results demonstrate that OXO exerts anti-
cancer activity through anti-angiogenesis and
tumor cell cycle arrest and apoptosis. These findings warrant additional studies of OXO as a novel agent for the
chemoprevention and treatment of
lung cancer.