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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 NOS inhibitor L-NAME on capillary formation by endothelial cells. Comparison of the capillary tube structure for endothelial cells treated by 2 mM of nitric oxide synthase inhibitor (b) with control well (a).
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Figure 5: Effect of NOS inhibitor L-NAME on capillary formation by endothelial cells. Comparison of the capillary tube structure for endothelial cells treated by 2 mM of nitric oxide synthase inhibitor (b) with control well (a).

Mentions: The next study was prepared to determine if nitric oxide inhibition could decrease the process of angiogenesis. To find the effect of NO inhibition on angiogenesis, cells incubated on Matrigel were exposed to L-NAME with concentrations 0.2–3 mM. Images of capillary type vessels were made after 24 h. An example of capillary tube formation in a control well and in a well with addition of 2 mM L-NAME is shown in Figure 5. Reduction of the formation of capillary-like structure by HUVECs and HUAECs cells after treatment by different concentrations of L-NAME is shown in Figure 6. The addition of L-NAME to medium with endothelial cells caused a dose dependent inhibition of angiogenesis, which ranged from 16% for 0.2 mM of reagent to 45% for 0.5–3 mM L-NAME. These data strongly suggest that NO formation is an important regulator of the angiogenic process. Use of a NOS inhibitor (L-NAME) markedly decreased the number of capillary tubes formed, thus decreasing angiogenesis.


Anti-angiogenic effect of high doses of ascorbic acid.

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

Effect of NOS inhibitor L-NAME on capillary formation by endothelial cells. Comparison of the capillary tube structure for endothelial cells treated by 2 mM of nitric oxide synthase inhibitor (b) with control well (a).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Effect of NOS inhibitor L-NAME on capillary formation by endothelial cells. Comparison of the capillary tube structure for endothelial cells treated by 2 mM of nitric oxide synthase inhibitor (b) with control well (a).
Mentions: The next study was prepared to determine if nitric oxide inhibition could decrease the process of angiogenesis. To find the effect of NO inhibition on angiogenesis, cells incubated on Matrigel were exposed to L-NAME with concentrations 0.2–3 mM. Images of capillary type vessels were made after 24 h. An example of capillary tube formation in a control well and in a well with addition of 2 mM L-NAME is shown in Figure 5. Reduction of the formation of capillary-like structure by HUVECs and HUAECs cells after treatment by different concentrations of L-NAME is shown in Figure 6. The addition of L-NAME to medium with endothelial cells caused a dose dependent inhibition of angiogenesis, which ranged from 16% for 0.2 mM of reagent to 45% for 0.5–3 mM L-NAME. These data strongly suggest that NO formation is an important regulator of the angiogenic process. Use of a NOS inhibitor (L-NAME) markedly decreased the number of capillary tubes formed, thus decreasing angiogenesis.

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