Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity
Abstract
:Simple Summary
Abstract
1. Introduction
2. Physiological and Anti-Tumor Activities of Vitamin C
3. Cancer Stem Cell Phenotypes and Plasticity
4. Metabolic Plasticity of Cancer Stem Cells
5. Anti-Cancer Mechanism of Vitamin C in Targeting Cancer Stem Cells
5.1. Targeting Leukemic Stem Cells with Vitamin C
5.2. Targeting Liver Cancer Stem Cells with Vitamin C
5.3. Targeting Breast Cancer Stem Cells with Vitamin C
5.4. Targeting Metabolic Plasticity in Pancreatic Cancer with Vitamin C
5.5. Targeting Cancer Stem Cells with Vitamin C in Combination Therapy
6. Conclusions
Funding
Conflicts of Interest
References
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Cancer Stem Cell Type/Origin | Methods | Results | Ref. |
---|---|---|---|
Hematopoietic stem cells (HSCs) purified from the bone marrow of mice (Gulo−/−, Tet2fl/fl, Flt3ITD, Slc23a2−/−) or bone marrow aspirates collected from patients, aged 34–85, who were being assessed for lymphoma | Human hematopoietic cell purification Bone marrow reconstitution assays HSC culture Metabolomics to measure 5 hmC, 5 mC, and C by LC–MS/MS RNA-sequencing (RNA-seq) analysis | HSCs have high Vitamin C (VC) levels and ascorbate depletion increases HSC frequency. VC depletion reduces Tet2 activity in HSCs and progenitors in vivo. Low VC levels cooperate with Flt3ITD to promote myelopoiesis, in part, by reducing TET2 function, and cell-autonomously promote HSC function. Low VC levels accelerate leukemogenesis. | Agathocleous, et al. [36] |
Primary mouse hematopoietic progenitor cells or bone marrow cells from TRE-TurboGFP-shTet2 and TRE-TurboGFP-shTet3 transgenic mice; Vav-tTA, Rosa-M2rtTA, and TRE-GFP-Ren mice; C57BL/6 B6.SJL-Ptprca Pepcb/BoyJ (CD45.1) mice; and germ-line Tet2-deficient mice Human leukemia cell lines: HL60, MOLM13, K562, KG1, THP1, and KASUMI1 Diagnostic bone marrow aspirates obtained from acute myeloid leukemia (AML) patients | Primary AML colony formation and liquid differentiation assays Bone marrow competitive transplantation Global DNA methylation quantitation, RNS sequencing, bisulfite sequencing analysis 5-hydroxymethylcytosine DNA immunoprecipitation (5 hmeDIP), sequencing, and analysis | TET2 restoration reverses aberrant self-renewal of Tet2-deficient cells. TET2 restoration promotes DNA demethylation, differentiation, and cell death. VC treatment mimics TET2 restoration to block leukemia progression. VC treatment enhances leukemia cell sensitivity to PARP inhibition. | Cimmino, et al. [35] |
Human hepatocellular carcinoma (HCC) and mouse liver cancer cells Patient-derived xenograft (PDX) liver tumors from human patients | Colony formation assays with HCC cells (HCC-LM3 and HuH-7 cells) and liver CSCs Cell viability and cell invasion assays Knockdown of SVCT-2 via shSVCT-2 plasmid transfection SVCT-2 immunohistochemistry staining in HCC tumors Microarrays In vivo xenograft assays using the HCC PDX model and PDXs | SVCT-2 is highly expressed in liver CSCs and is required for the maintenance of liver CSCs. SVCT-2 determines the differential susceptibility to pharmacological VC-induced cell death. Pharmacological VC (10 mM) preferentially eradicates liver CSCs in vitro. SVCT-2-dependent mechanisms of pharmacological VC-induced cell death. Pharmacological VC (4 g/kg) impairs tumor growth and eradicates liver CSCs in vivo. | Lv, et al. [37] |
Huh7 and Hep3B HCC cell lines | 3D sphere formation and colony formation assays Cell viability analysis RT-qPCR H2O2 Assays In vivo xenograft assays | VC (0.5~1 mM) selectively inhibits the viability of liver cancer cells and liver CSCs in vitro. VC inhibits sphere formation and colony formation in liver cancer cells. VC (4 g/kg) prevents HCC xenograft tumor growth and metastasis in vivo. | Wan, et al. [38] |
MCF7 human breast cancer cell line | CSC identification with a mitochondrial metabolism reporter (mPGC1α-eGFP-Puro-R) and NADH auto-fluorescence analysis 3D mammosphere formation assays Mitochondrial ROS/H2O2 detection assays Cell migration: in vitro scratch assays Metabolic flux analysis (MFA) | Mitochondrial biogenesis indicated by PGC1α reporter activity correlates with stemness. Increased mitochondrial ROS levels and H2O2 production contribute to stemness. Increased NAD(P)H levels directly correlate with stemness. VC (1~2 mM) blocks mammosphere formation. | Bonuccelli, et al. [39] |
MDA-MB-231 and MDA-MB-468 Triple-negative breast cancer (TNBC) stem cells | Fluorescence-activated cell sorting (FACS) of CSC populations (CD44+/24−) Population doubling time (PDT)/cell proliferation assays Detection of ROS generation in CD44+/24− CSCs via fluorescence microscopy and nitroblue tetrazolium (NBT) assays Mitotracker staining assays and JC-1 staining for qualitative assessments of mitochondrial integrity and membrane potential (ΔΨm) | Breast CSC yields are ~80% from TNBC cell lines with different morphologies and similar doubling times. Treatment with VC (10~20 mM) leads to changes in morphology followed by proliferation inhibition in breast CSCs. VC-induced ROS production and mitochondrial damage in sorted breast CSCs occurs in a dose dependent manner, with pronounced effects on MDA-MB-231 CSCs compared to MDA-MB-468 CSCs. The antioxidant activities/redox alterations that occur upon VC treatment are correlated with the VC sensitivities of the CSCs. | Sen, et al. [40] |
CT26, MC38, and 4T1 murine carcinoma cells | Synthesis and characterization of nanocarrier particles (NCPs): Carboplatin (Carb)/Docetaxel (DTX) and Oxaliplatin (OX)/SN-38 (active metabolite of irinotecan) Flow cytometry analysis of pluripotency factors (SOX2, OCT4, and NANOG) 3D sphere formation assays Metabolic flux analysis with fluorescence lifetime imaging microscopy (FLIM)/GAPDH activity assays/mitochondrial morphology and membrane potential assessments In vitro apoptosis/cytotoxicity assays In vivo orthotopic xenografts and measurements of tumor growth/metastasis | VC (5 mM) enhances the cytotoxicity of NCPs against CSCs in vitro. VC transitions CSCs from glycolysis to mtOXPHOS and inhibits CSC self-renewal. VC (4 g/kg) potentiates the antitumor efficacy of NCPs and reduces tumor cell stemness in vivo. VC and NCPs in combination treatments prevent post-surgery relapse and inhibit systemic metastasis. | Jiang, et al. [41] |
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Lee, Y. Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity. Cancers 2023, 15, 5657. https://doi.org/10.3390/cancers15235657
Lee Y. Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity. Cancers. 2023; 15(23):5657. https://doi.org/10.3390/cancers15235657
Chicago/Turabian StyleLee, Yool. 2023. "Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity" Cancers 15, no. 23: 5657. https://doi.org/10.3390/cancers15235657