6‐(1‐Oxobutyl)‐5,8‐dimethoxy‐1,4‐naphthoquinone inhibits lewis lung cancer by antiangiogenesis and apoptosis

Abstract

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-1a 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-1a 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. ' 2007 Wiley-Liss, Inc.Key words: angiogenesis; HIF-1 alpha; VEGF; apoptosis; lung cancer Lung cancer is the leading cause of cancer mortality worldwide, 1 including the United States (US). 2 The survival benefit of current cytotoxic cancer therapeutic drugs is very dismal in spite of serious drug side effects. As in many other solid cancers, lung cancer development (carcinogenesis) is a multiple step process that involves alterations of many molecular and cellular pathways regulating cancer cell proliferation, survival (anti-apoptosis) as well as neo-angiogenesis. Induction of apoptosis by chemopreventive agents can lead to the elimination of pre-neoplastic cells, affording a permanent protection against carcinogenesis. 3,4 Most anticancer therapy drugs induce apoptosis to achieve therapeutic efficacy. Novel and nontoxic agents that exert selective multi-targeting actions on cancer cell cycle progression and apoptosis as well as neo-angiogenesis will be important to combat this deadly disease through chemoprevention and innovative treatment.Much work in the past decades has convincingly supported the obligatory need of angiogenesis for solid tumor growth and progression. 3,[5][6][7] Hypoxia commonly develops within solid tumors because the rate of tumor cell proliferation is out-pacing the rate of blood vessel formation. 8 Hypoxia is a potent ...

PKCδ and cofilin activation affects peripheral actin reorganization and cell-cell contact in cells expressing integrin α5 but not its tailless mutant

“…Since, (1) we failed to find any growth factors (including 100 ng/ml hepatocyte growth factor) or cytokines capable of causing RIE1-␣5 cells to scatter and (2) cell scattering involves cell-cell contact disruption, presumably via actin-reorganization-based morphological changes, we investigated if a reagent-mediated actin reorganization might cause cell-cell contact loss in cells with integrin ␣5 WT or its tailless mutant expression. A putative anti-tumorigenic reagent (Lee et al, 2007), 6-(1-oxobutyl)-5,8-dimethoxy-1,4- Fig. 1.…”

Sequential Delivery of Basic Fibroblast Growth Factor and Platelet-Derived Growth Factor for Angiogenesis

“…[20][21][22][23] The ends of the hollow fiber remain exposed, providing access to the contents of the lumen of the fiber (and consequently what is delivered) over the course of experimentation. Using this system, we were able to achieve sequential delivery of two different angiogenic instructions: (1) vascular endothelial growth factor (VEGF; involved in vasculature permeability/destabilization 24 and endothelial cell recruitment 6 ) and (2) sphingosine-1-phosphate (S1P; promoting vessel stabilization in vivo 25,26 and involved in a reduction in endothelial cell migration 27,28 ). In this prior study, when VEGF delivery was followed by delivery of S1P, we observed significantly greater endothelial cell migration as well as substantial increases in vessel maturity, when compared to single or dual delivery of these factors.…”

Compound K Inhibits Basic Fibroblast Growth Factor-Induced Angiogenesis via Regulation of p38 Mitogen Activated Protein Kinaseand AKT in Human Umbilical Vein Endothelial Cells

“…24,25) Likewise, anti-angiogenic activities by paonol, shikonin, campesterol, heyneanol A and 6-(1-oxobutyl)-5,8-dimethoxy-1,4-naphthoquinone, Korean Angelica gigas and Kamikaekyuktang, Shiquandabutangjiaweibang and Bojungbangdoktang were demonstrated by our group. [26][27][28][29][30][31][32][33] In the present study, we have investigated whether or not CK can inhibit bFGF-mediated angiogenesis and its related signaling pathways in HUVECs.…”