Opposing effects of low versus high concentrations of water soluble vitamins/dietary ingredients Vitamin C and niacin on colon cancer stem cells (CSCs)

Sen, Utsav; P, Sudheer Shenoy; Bose, Bipasha

doi:10.1002/cbin.10830

Cited by 23 publications

(17 citation statements)

References 49 publications

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“…In the present study, NAM showed a strong and significant antiproliferation effect on A375 and SK-MEL-28 melanoma cells, two human melanoma cell lines characterized for high and low aggressiveness, respectively [ 37 ]. NAM was tested in the mM concentration range since similar high concentrations have recently shown activity in melanoma cells [ 23 ] and in colon cancer cells [ 51 ]. In the latter cells low- and high-doses of NAM show opposite effects; micromolar doses appear to be cell-protective while millimolar doses induce cell death, likely related to the oxidative stress [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…NAM was tested in the mM concentration range since similar high concentrations have recently shown activity in melanoma cells [ 23 ] and in colon cancer cells [ 51 ]. In the latter cells low- and high-doses of NAM show opposite effects; micromolar doses appear to be cell-protective while millimolar doses induce cell death, likely related to the oxidative stress [ 51 ]. Cell killing effects of high NAM doses were also observed in C. elegans with defective activity of nicotinamidase PNC-1, where NAM levels increase tenfold [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

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Nicotinamide inhibits melanoma in vitro and in vivo

Scatozza

Moschella

D’Arcangelo

et al. 2020

J Exp Clin Cancer Res

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Background Even though new therapies are available against melanoma, novel approaches are needed to overcome resistance and high-toxicity issues. In the present study the anti-melanoma activity of Nicotinamide (NAM), the amide form of Niacin, was assessed in vitro and in vivo. Methods Human (A375, SK-MEL-28) and mouse (B16-F10) melanoma cell lines were used for in vitro investigations. Viability, cell-death, cell-cycle distribution, apoptosis, Nicotinamide Adenine Dinucleotide+ (NAD+), Adenosine Triphosphate (ATP), and Reactive Oxygen Species (ROS) levels were measured after NAM treatment. NAM anti-SIRT2 activity was tested in vitro; SIRT2 expression level was investigated by in silico transcriptomic analyses. Melanoma growth in vivo was measured in thirty-five C57BL/6 mice injected subcutaneously with B16-F10 melanoma cells and treated intraperitoneally with NAM. Interferon (IFN)-γ-secreting murine cells were counted with ELISPOT assay. Cytokine/chemokine plasmatic levels were measured by xMAP technology. Niacin receptors expression in human melanoma samples was also investigated by in silico transcriptomic analyses. Results NAM reduced up to 90% melanoma cell number and induced: i) accumulation in G1-phase (40% increase), ii) reduction in S- and G2-phase (about 50% decrease), iii) a 10-fold increase of cell-death and 2.5-fold increase of apoptosis in sub-G1 phase, iv) a significant increase of NAD+, ATP, and ROS levels, v) a strong inhibition of SIRT2 activity in vitro. NAM significantly delayed tumor growth in vivo (p ≤ 0.0005) and improved survival of melanoma-bearing mice (p ≤ 0.0001). About 3-fold increase (p ≤ 0.05) of Interferon-gamma (IFN-γ) producing cells was observed in NAM treated mice. The plasmatic expression levels of 6 cytokines (namely: Interleukin 5 (IL-5), Eotaxin, Interleukin 12 (p40) (IL12(p40)), Interleukin 3 (IL-3), Interleukin 10 (IL-10) and Regulated on Activation Normal T Expressed and Secreted (RANTES) were significantly changed in the blood of NAM treated mice, suggesting a key role of the immune response. The observed inhibitory effect of NAM on SIRT2 enzymatic activity confirmed previous evidence; we show here that SIRT2 expression is significantly increased in melanoma and inversely related to melanoma-patients survival. Finally, we show for the first time that the expression levels of Niacin receptors HCAR2 and HCAR3 is almost abolished in human melanoma samples. Conclusion NAM shows a relevant anti-melanoma activity in vitro and in vivo and is a suitable candidate for further clinical investigations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nicotinamide inhibits melanoma in vitro and in vivo

Scatozza

Moschella

D’Arcangelo

et al. 2020

J Exp Clin Cancer Res

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“…Opposing effects of low (5-25 μM) and high (100-1000 μM) concentrations of vitamin C were observed in cancer stem cells (CSCs) fractionated from the human colorectal cancer cell line HT-29 [126]. At low concentrations, vitamin C stimulated proliferation of CSCs, but it did not affect nonstem cancer cells and normal fibroblasts.…”

Section: Cancer Stem Cellsmentioning

confidence: 98%

Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations

Pawłowska

Szczepańska

Błasiak

2019

Oxidative Medicine and Cellular Longevity

101

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Vitamin C is an antioxidant that may scavenge reactive oxygen species preventing DNA damage and other effects important in cancer transformation. Dietary vitamin C from natural sources is taken with other compounds affecting its bioavailability and biological effects. High pharmacological doses of vitamin C may induce prooxidant effects, detrimental for cancer cells. An oxidized form of vitamin C, dehydroascorbate, is transported through glucose transporters, and cancer cells switch from oxidative phosphorylation to glycolysis in energy production so an excess of vitamin C may limit glucose transport and ATP production resulting in energetic crisis and cell death. Vitamin C may change the metabolomic and epigenetic profiles of cancer cells, and activation of ten-eleven translocation (TET) proteins and downregulation of pluripotency factors by the vitamin may eradicate cancer stem cells. Metastasis, the main reason of cancer-related deaths, requires breakage of anatomical barriers containing collagen, whose synthesis is promoted by vitamin C. Vitamin C induces degradation of hypoxia-inducible factor, HIF-1, essential for the survival of tumor cells in hypoxic conditions. Dietary vitamin C may stimulate the immune system through activation of NK and T cells and monocytes. Pharmacological doses of vitamin C may inhibit cancer transformation in several pathways, but further studies are needed to address both mechanistic and clinical aspects of this effect.

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“…La supresión de la respiración debida a los altos niveles de glucosa se conoce como efecto de Crabtree, pero no se sabe todavía si los procesos celulares responsables de esta inhibición (que es muy rápida, ocurre en segundos), son los mismos, o similares, para levaduras y las células cancerígenas (Hagman, et al, 2014;Pfeiffer & Morley, 2014;Hammad, et al, 2016). En estudios recientes se ha confirmado el efecto anticancerígeno del ácido ascórbico en concentraciones altas (Sen, et al, 2017;Xia, et al, 2017;Mastrangelo, et al, 2017), aunque el mecanismo no es todavía claro. No se descarta que ello se deba a la tendencia a generar potencial negativo de la membrana externa por la oxidación de ascorbato, como se muestra en la Figura 1B.…”

Section: Generación Del Potencial De La Membrana Mitocondrial Externaunclassified

El papel de la membrana mitocondrial externa en el control del metabolismo energético celular

Lemeshko

2018

Rev. Acad. Colomb. Cienc. Ex. Fis. Nat.

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Hasta 95 % de la energía en las células eucariotas se produce en las mitocondrias, las cuales se componen de dos membranas, la interna y la externa. La principal función de la membrana interna es la fosforilación oxidativa. El trifosfato de adenosina (adenosine triphosphate, ATP) y el fosfato de creatina, producidos en las mitocondrias, se transfieren al citosol atravesando la membrana mitocondrial externa, básicamente a través de las porinas (voltagedependent anion cannel, VDAC). Dado que los mecanismos de generación del potencial eléctrico en esta membrana se desconocen, generalmente se asume que la compuerta eléctrica de los VDAC siempre está abierta. Sin embargo, el potencial de la membrana mitocondrial externa puede generarse de manera dependiente del metabolismo energético celular mediante diversos mecanismos. La generación de dicho potencial mediante los complejos VDAC-hexocinasa en las células cancerígenas, o la oxidación directa del NADH citosólico en las mitocondrias de la levadura Saccharomyces cerevisiae permiten explicar los efectos de Crabtree y Warburg como una supresión eléctrica de las mitocondrias. Según el modelo desarrollado, la prevención de la formación de los complejos VDAC-hexocinasa por acción de algunos factores podría causar efectos anti-Warburg y anticancerígenos. Además, este potencial positivo generado por los complejos VDAC-creatina-cinasa podría proteger las mitocondrias de los cardiomiocitos y de otras células frente a los niveles tóxicos de calcio en el citosol. Los mecanismos propuestos de generación del potencial de la membrana dependiente del metabolismo energético celular, sugieren que las propiedades eléctricas del VDAC tienen un papel importante en varios procesos fisiológicos y patofisiológicos. © 2018. Acad. Colomb. Cienc. Ex. Fis. Nat.

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Opposing effects of low versus high concentrations of water soluble vitamins/dietary ingredients Vitamin C and niacin on colon cancer stem cells (CSCs)

Cited by 23 publications

References 49 publications

Nicotinamide inhibits melanoma in vitro and in vivo

Nicotinamide inhibits melanoma in vitro and in vivo

Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations

El papel de la membrana mitocondrial externa en el control del metabolismo energético celular

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