Abstract:Pharmacologic ascorbate treatment (P-AscH À , high-dose, intravenous vitamin C) results in a transient short-term increase in the flux of hydrogen peroxide that is preferentially cytotoxic to cancer cells versus normal cells. This study examines whether an increase in hydrogen peroxide is sustained posttreatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH À was examined in tumorigenic and nontumorigenic cells. P-AscH À resulted in sustained… Show more
“…We showed that 250 μM AA selectively induced cell death in primary leukemic CLL B-cells by acting as a pro-oxidant and thus by leading to the release of H 2 O 2 into the extracellular medium. These results are in compliance with previous observations in other cancers [ 5 , 12 , 14 ]. The cytotoxic effect of AA via H 2 O 2 generation was confirmed using an H 2 O 2 formation inhibitor (the iron chelator DFX) and two H 2 O 2 scavengers (catalase and SP).…”
Section: Discussionsupporting
confidence: 93%
“…Along with the superoxide anion (O 2 •− ) and the hydroxyl radical ( • OH), H 2 O 2 is a ROS. The literature data show that ROS (including H 2 O 2 ) mediate apoptosis through increasing the level of oxidative stress in cancer cells [ 14 , 15 , 52 ]. Indeed, targeting intracellular redox homeostasis by increasing ROS levels in cancer cells is a promising treatment approach [ 15 ].…”
Section: Discussionmentioning
confidence: 99%
“…This leads to the generation of cytotoxic hydrogen peroxide (H 2 O 2 , i.e. a reactive oxygen species (ROS)) [ 5 , 12 , 14 ]. High concentrations of ROS are cytotoxic, via damage to DNA and mitochondria and the activation of apoptotic pathways [ 15 ].…”
Background
Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions.
Methods
Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated.
Results
Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells. Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL.
Conclusion
These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.
“…We showed that 250 μM AA selectively induced cell death in primary leukemic CLL B-cells by acting as a pro-oxidant and thus by leading to the release of H 2 O 2 into the extracellular medium. These results are in compliance with previous observations in other cancers [ 5 , 12 , 14 ]. The cytotoxic effect of AA via H 2 O 2 generation was confirmed using an H 2 O 2 formation inhibitor (the iron chelator DFX) and two H 2 O 2 scavengers (catalase and SP).…”
Section: Discussionsupporting
confidence: 93%
“…Along with the superoxide anion (O 2 •− ) and the hydroxyl radical ( • OH), H 2 O 2 is a ROS. The literature data show that ROS (including H 2 O 2 ) mediate apoptosis through increasing the level of oxidative stress in cancer cells [ 14 , 15 , 52 ]. Indeed, targeting intracellular redox homeostasis by increasing ROS levels in cancer cells is a promising treatment approach [ 15 ].…”
Section: Discussionmentioning
confidence: 99%
“…This leads to the generation of cytotoxic hydrogen peroxide (H 2 O 2 , i.e. a reactive oxygen species (ROS)) [ 5 , 12 , 14 ]. High concentrations of ROS are cytotoxic, via damage to DNA and mitochondria and the activation of apoptotic pathways [ 15 ].…”
Background
Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions.
Methods
Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated.
Results
Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells. Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL.
Conclusion
These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.
“…1 B–D) suggesting that peroxide mediates this effect. Previous studies from our laboratory have demonstrated that PDAC cells are viable at this time point 12 , 13 , which further supports the hypothesis that P-AscH − induced generation of H 2 O 2 mediates the inhibition of PDAC invasion as opposed to killing the cells which would indirectly inhibit invasion. Figure 1 P-AscH − attenuates the invasive phenotype of PDAC in vitro .…”
Pharmacological ascorbate (P-AscH−, high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans. Phase I studies in pancreatic cancer (PDAC) utilizing P-AscH− have demonstrated increases in progression free survival, suggesting a reduction in metastatic disease burden. The purpose of this study was to determine the effects of P-AscH− on metastatic PDAC. Several in vitro and in vivo mechanisms involved in PDAC metastases were investigated following treatment with P-AscH−. Serum from PDAC patients in clinical trials with P-AscH− were tested for the presence and quantity of circulating tumor cell-derived nucleases. P-AscH− inhibited invasion, basement membrane degradation, decreased matrix metalloproteinase expression, as well as clonogenic survival and viability during exposure to fluid shear stress. In vivo, P-AscH− significantly decreased formation of ascites, tumor burden over time, circulating tumor cells, and hepatic metastases. Both in vitro and in vivo findings were reversed with the addition of catalase suggesting that the effect of P-AscH− on metastatic disease is mediated by hydrogen peroxide. Finally, P-AscH− decreased CTC-derived nucleases in subjects with stage IV PDAC in a phase I clinical trial. We conclude that P-AscH− attenuates the metastatic potential of PDAC and may prove to be effective for treating advanced disease.
“…Specifically, it has been postulated that the megadoses of AA, in the presence of metals, favor the Fenton reaction and the subsequent extracellular production of H 2 O 2 [ 7 , 31 , 32 , 86 ]. Diffusion of H 2 O 2 from the extracellular medium could be the trigger for an overwhelming overload of intracellular ROS, which would favor tumor death due to conventional necrosis [ 31 , 86 , 87 ]. It is important to note that this mechanism only works with megadoses of AA, because during the diffusion of H 2 O 2 , it is diluted 100-fold [ 88 ]; therefore, high concentrations of AA are needed to produce a lethal amount of H 2 O 2 .…”
Section: Regulation Of Cell Death By Vitamin Cmentioning
Historically, vitamin C has been associated with many regulatory processes that involve specific signaling pathways. Among the most studied signaling pathways are those involved in the regulation of aging, differentiation, neurotransmission, proliferation, and cell death processes in cancer. This wide variety of regulatory effects is due to the fact that vitamin C has a dual mechanism of action. On the one hand, it regulates the expression of genes associated with proliferation (Ccnf and Ccnb1), differentiation (Sox-2 and Oct-4), and cell death (RIPK1 and Bcl-2). At the same time, vitamin C can act as a regulator of kinases, such as MAPK and p38, or by controlling the activation of the NF-kB pathway, generating chronic responses related to changes in gene expression or acute responses associated with the regulation of signal transduction processes. To date, data from the literature show a permanent increase in processes regulated by vitamin C. In this review, we critically examine how vitamin C regulates these different cellular programs in normal and tumor cells.
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