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Anti-angiogenic effect of high doses of ascorbic acid.

Mikirova NA, Ichim TE, Riordan NH - J Transl Med (2008)

Bottom Line: We hypothesized that AA may exert anti-angiogenic effects.The results of these experiments showed an inverse correlation between AA concentrations relative to both cell migration and gap filling capacity.Suppression of NO (nitric oxide) generation appeared to be one of the mechanisms by which AA mediated angiostatic effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bio-Communications Research Institute, Wichita, Kansas, USA. nmikirova@brightspot.org

ABSTRACT
Pharmaceutical doses of ascorbic acid (AA, vitamin C, or its salts) have been reported to exert anticancer activity in vitro and in vivo. One proposed mechanism involves direct cytotoxicity mediated by accumulation of ascorbic acid radicals and hydrogen peroxide in the extracellular environment of tumor cells. However, therapeutic effects have been reported at concentrations insufficient to induce direct tumor cell death. We hypothesized that AA may exert anti-angiogenic effects. To test this, we expanded endothelial progenitor cells (EPCs) from peripheral blood and assessed, whether or not high dose AA would inhibit EPC ability to migrate, change energy metabolism, and tube formation ability. We also evaluated the effects of high dose AA on angiogenic activities of HUVECs (human umbilical vein endothelial cells) and HUAECs (human umbilical arterial endothelial cells). According to our data, concentrations of AA higher than 100 mg/dl suppressed capillary-like tube formation on Matrigel for all cells tested and the effect was more pronounced for progenitor cells in comparison with mature cells. Co-culture of differentiated endothelial cells with progenitor cells showed that there was incorporation of EPCs in vessels formed by HUVECs and HUAECs. Cell migration was assessed using an in vitro wound healing model. The results of these experiments showed an inverse correlation between AA concentrations relative to both cell migration and gap filling capacity. Suppression of NO (nitric oxide) generation appeared to be one of the mechanisms by which AA mediated angiostatic effects. This study supports further investigation into non-cytotoxic antitumor activities of AA.

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Effect of high doses of ascorbic acid on capillary tube formation by mature endothelial cells. Capillary tube formation by HUVECs in control well without addition of ascorbate (a) and in well treated by 3 mg/ml of ascorbic acid (b).
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Figure 2: Effect of high doses of ascorbic acid on capillary tube formation by mature endothelial cells. Capillary tube formation by HUVECs in control well without addition of ascorbate (a) and in well treated by 3 mg/ml of ascorbic acid (b).

Mentions: To prove that AA has an effect on endothelial tube formation capacity, we used in vitro assays of capillary tube formation on Matrigel. Experiments were performed for several concentrations of serum in medium (2%–100%). AA was added to the culture well at the time of cell plating. Formation of tube vessels started after 1 hour of incubation while tube vessel formation with capillary loops were seen after 3 hours of incubation. This occurred for all endothelial cell lines used: HUVECs; HUAECs; and EPCs. However, as the AA concentration increased past the 50–100 mg/ml point, the number of capillary loops formed began to decrease in number for all cell lines (Figures 1, 2). Figure 1 shows the effect of high doses of ascorbic acid on capillary formation by endothelial progenitor cells. The images are presented for control well (a) and well with cells treated by 300 mg/dl of ascorbic acid (b). Effect of high doses of ascorbic acid on tube formation by mature endothelial cells is shown in Figure 2 for control well (a) and well with 300 mg/dl ascorbic acid added.


Anti-angiogenic effect of high doses of ascorbic acid.

Mikirova NA, Ichim TE, Riordan NH - J Transl Med (2008)

Effect of high doses of ascorbic acid on capillary tube formation by mature endothelial cells. Capillary tube formation by HUVECs in control well without addition of ascorbate (a) and in well treated by 3 mg/ml of ascorbic acid (b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2562367&req=5

Figure 2: Effect of high doses of ascorbic acid on capillary tube formation by mature endothelial cells. Capillary tube formation by HUVECs in control well without addition of ascorbate (a) and in well treated by 3 mg/ml of ascorbic acid (b).
Mentions: To prove that AA has an effect on endothelial tube formation capacity, we used in vitro assays of capillary tube formation on Matrigel. Experiments were performed for several concentrations of serum in medium (2%–100%). AA was added to the culture well at the time of cell plating. Formation of tube vessels started after 1 hour of incubation while tube vessel formation with capillary loops were seen after 3 hours of incubation. This occurred for all endothelial cell lines used: HUVECs; HUAECs; and EPCs. However, as the AA concentration increased past the 50–100 mg/ml point, the number of capillary loops formed began to decrease in number for all cell lines (Figures 1, 2). Figure 1 shows the effect of high doses of ascorbic acid on capillary formation by endothelial progenitor cells. The images are presented for control well (a) and well with cells treated by 300 mg/dl of ascorbic acid (b). Effect of high doses of ascorbic acid on tube formation by mature endothelial cells is shown in Figure 2 for control well (a) and well with 300 mg/dl ascorbic acid added.

Bottom Line: We hypothesized that AA may exert anti-angiogenic effects.The results of these experiments showed an inverse correlation between AA concentrations relative to both cell migration and gap filling capacity.Suppression of NO (nitric oxide) generation appeared to be one of the mechanisms by which AA mediated angiostatic effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bio-Communications Research Institute, Wichita, Kansas, USA. nmikirova@brightspot.org

ABSTRACT
Pharmaceutical doses of ascorbic acid (AA, vitamin C, or its salts) have been reported to exert anticancer activity in vitro and in vivo. One proposed mechanism involves direct cytotoxicity mediated by accumulation of ascorbic acid radicals and hydrogen peroxide in the extracellular environment of tumor cells. However, therapeutic effects have been reported at concentrations insufficient to induce direct tumor cell death. We hypothesized that AA may exert anti-angiogenic effects. To test this, we expanded endothelial progenitor cells (EPCs) from peripheral blood and assessed, whether or not high dose AA would inhibit EPC ability to migrate, change energy metabolism, and tube formation ability. We also evaluated the effects of high dose AA on angiogenic activities of HUVECs (human umbilical vein endothelial cells) and HUAECs (human umbilical arterial endothelial cells). According to our data, concentrations of AA higher than 100 mg/dl suppressed capillary-like tube formation on Matrigel for all cells tested and the effect was more pronounced for progenitor cells in comparison with mature cells. Co-culture of differentiated endothelial cells with progenitor cells showed that there was incorporation of EPCs in vessels formed by HUVECs and HUAECs. Cell migration was assessed using an in vitro wound healing model. The results of these experiments showed an inverse correlation between AA concentrations relative to both cell migration and gap filling capacity. Suppression of NO (nitric oxide) generation appeared to be one of the mechanisms by which AA mediated angiostatic effects. This study supports further investigation into non-cytotoxic antitumor activities of AA.

Show MeSH
Related in: MedlinePlus