Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells
Abstract
:1. Introduction
2. Cancer Stem Cell Metabolism
3. Vitamin C/Ascorbic Acid—Metabolism and Chemistry of Vitamin C
4. Transporters of Vit.C
5. Evidence for Vit.C Effect in Cancer Treatment
6. Vit.C and Its Anticancer Mechanism
6.1. Redox Imbalance
6.1.1. Increased Levels of Labile Metals Like Iron
6.1.2. DHA Uptake Instead of Glucose
6.2. Ten Eleven Translocation (TET)—Cancer and Effect of Vit.C (Targeting Epigenetic Regulators)
6.3. Hypoxia-Inducible Factor (HIF)—Cancer and Effect of Vit.C
7. Synergetic Effect of Vit.C on Energy Metabolism in Cancer Stem Cells
8. Role of Vit.C in Cancer Epigenome Regulation
9. Future Studies on Vit.C on Cancer Stem Cells
10. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
OH | Hydroxyl radical |
α-KGDDs | alpha-ketoglutarate dependent dioxygenases |
5-caC | 5-carboxycytosine |
5-fC | 5-formylcytosine |
5-hmC | 5-hydroxymethylcytosine |
5-mC | 5-methylcytosine |
AKT | Protein kinase B |
ALDH | Aldehyde dehydrogenase |
BRAF | B-Raf proto-oncogene, serine/threonine kinase |
CD | Cluster of differentiation |
CSCs | Cancer stem cells |
Cu2+ | Cupric ion |
CXCR4 | C-X-C chemokine receptor type 4 |
d-TPP | Dodecyl—tri-phenyl-phosphonium |
DHA | Dehydroascorbic acid |
DNMT | DNA methyltransferase |
EMT | Epithelial-mesenchymal transition |
ESCs | Embryonic stem cells |
Fe2+ | Ferrous ion |
GAPDH | Glyceraldehyde-phosphate dehydrogenase |
GLUT | Glucose transporter |
H2O2 | Hydrogen peroxide |
HCC | Hepatocellular carcinoma |
HIF1α | Hypoxia-inducible factor 1 alpha |
IC-50 | Inhibitory concentration |
IDH | Isocitrate dehydrogenase |
iPS | Induced pluripotent stem cells |
JAK | Janus kinase |
JHDM | Jumonji-C domain-containing histone demethylases |
KRAS | KRAS proto-oncogene, GTPase |
LGR5 | Leucine-rich repeat-containing G-protein coupled receptor 5 |
miRNA | MicroRNA |
mTOR | Mammalian target of rapamycin |
NAD+ | Nicotinamide adenine dinucleotide |
NADPH | Nicotinamide adenine dinucleotide phosphate |
PARP | Poly (ADP-ribose) polymerase |
PBMC | Peripheral blood mononuclear cells |
PI3K | Phosphatidylinositol-4,5-bisphosphate 3-kinase |
ROS | Reactive oxygen species |
SCVT1/2 | Sodium dependent Vit.C transporter 1/2 |
STAT | Signal transducer and activator of transcription |
TET | Ten eleven translocation |
TPP | Tri-phenyl-phosphonium |
Vit.C | Vitamin C |
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Type | In Vitro/In Vivo | Status/Month Year | Drugs | Reference | CSC Markers | Reference | miRNA in CSC | Reference |
---|---|---|---|---|---|---|---|---|
Breast Cancer | In vivo, Population based cohort | Completed/April 2006 | Chemotherapy, Radiation, Vit.C/E, Multivitamin | [15] | ALDH1 | [2,16,17] | miR-495 | [18,19] |
In vitro, MCF-7 cells | Published/2019 | Doxycycline, Azithromycin, Vit.C | [20] | CD44 | [2,16,21] | miR-7 | [22,23] | |
CD24 | [16] | miR-34a | [22,24] | |||||
CD133 | [16] | miR-181 | [18,25] | |||||
CD90 | [16] | |||||||
α6-integrin | [16] | |||||||
Hedgehog-Gli activity | [16] | |||||||
Pancreatic Cancer | In vivo/Phase 2 (NCT01905150) | Completed/March 2019 | G-FLIP/G-FLIP-DM + Vit.C | [26] | ABCG2 | [2,16,27] | miR-1246 | [16,28] |
In vivo, Phase 1/2 (NCT03410030) | Ongoing/July 2020 | Vit.C + Nanoparticle + Paclitaxel + Cisplatin + Gemcitabine | [29] | ALDH1 | [2,16,30] | miR-210 | [16,31] | |
In vivo, Phase 2 (NCT03146962) | Ongoing/December 2021 | High dose Vit.C | [32] | CD24 | [16] | miR-21 | [16,31] | |
CD44 | [2,16,33] | Let-7 | [16,34] | |||||
CD133 | [2,16,35] | miR-200 family | [16,34] | |||||
C-Met | [16] | miR-200a | [16,36] | |||||
CXCR4 | [16] | miR-143/145 cluster | [16,37] | |||||
Nestin | [16] | miR-145 | [16,34] | |||||
Nodal-Activin | [16] | miR-34 family | [16,38] | |||||
Ovarian Cancer | In vivo, Phase 1/2 (NCT00228319) | Completed/August 2007 | Paclitaxel + Carboplatin + Sodium Ascorbate + Vit.C, A & E | [39] | CD24 | [16] | ||
CD44 | [2,16,40] | |||||||
CD177 | [16] | |||||||
CD133 | [2,16,41] | |||||||
Glioma/Glioblastoma | In vivo, Phase 2 (NCT02344355) | Ongoing/December 2023 | Radiation + temozolomide + Vit.C | [42] | CD15 | [16] | miR-145 | [22,43] |
CD90 | [16] | miR-21 | [22,44] | |||||
CD133 | [16] | miR-18 | [18,45] | |||||
Nestin | [16] | miR-204 | [18,46] | |||||
α6-integrin | [16] | miR-128 | [18,47] | |||||
miR-23b | [18,48] | |||||||
Lung Cancer | In vivo, Phase 2 (NCT03146962) | Ongoing/December 2021 | High dose Vit.C | [32] | ABCG2 | [2,16,49] | miR-145 | [22,50] |
In vivo, Phase 2 (NCT02420314) | Ongoing/December 2025 | Paclitaxel, Carboplatin + Vit.C | [51] | ALDH1 | [2,16,52] | miR-191 | [18,53] | |
In vivo, Phase 2 (NCT02905591) | Ongoing/July 2026 | Radiation Therapy + Paclitaxel, Carboplatin + Vit.C | [54] | CD90 | [16] | miR-487b | [18,55] | |
CD177 | [16] | |||||||
CD133 | [2,16,56] | |||||||
Colon Cancer | In vivo, Phase 2 (NCT03146962) | Ongoing/December 2021 | Vit.C | [32] | ABCB5 | [16] | Let-7 | [18,34,57] |
ALDH1 | [2,16,58] | |||||||
CD24 | [16] | |||||||
CD26 | [16] | |||||||
CD29 | [16] | |||||||
CD44 | [2,16,59] | |||||||
CD133 | [2,16,60] | |||||||
CD166 | [16] | |||||||
LGR5 | [16] | |||||||
β-catenin activity | [16] | |||||||
Leukemia | In vivo, Phase 2 (NCT03397173) | Ongoing/January 2020 | Azacitidine + Vit.C | [61] | miR-27a | [18,62] | ||
In vivo, Phase 2 (NCT03613727) | Ongoing/October 2022 | Vit.C | [63] | |||||
Lymphoma | In vivo, Phase 2 (NCT03418038) | Ongoing/March 2024 | Salvage Chemotherapy + Vit.C | [64] | ||||
In vivo, Phase 2 (NCT03613727) | Ongoing/October 2022 | Vit.C | [63] | |||||
Myeloid Leukemia | In vivo, Phase 2 (NCT03397173) | Ongoing/January 2020 | Azacitidine + Vit.C | [61] | miR-130b | [18,65] | ||
In vivo, Phase 2 (NCT03613727) | Ongoing/October 2022 | Vit.C | [63] | miR-29a | [18,66] | |||
miR-326 | [18,67] | |||||||
miR-150 | [18,68] | |||||||
Prostate Cancer | In vivo, Phase 2 (NCT02516670) | Ongoing/January 2030 | Docetaxel + Vit.C | [69] | ALDH1 | [2,16,70] | miR-7 | [22,71] |
CD44 | [2,16,72] | miR-34a | [22,73] | |||||
CD133 | [2,16,74] | |||||||
CD166 | [16] | |||||||
Trop2 | [16] | |||||||
α2β1Integrin | [16] | |||||||
α1Integrin | [16] | |||||||
ABCG2 | [2,75] |
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Satheesh, N.J.; Samuel, S.M.; Büsselberg, D. Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells. Biomolecules 2020, 10, 79. https://doi.org/10.3390/biom10010079
Satheesh NJ, Samuel SM, Büsselberg D. Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells. Biomolecules. 2020; 10(1):79. https://doi.org/10.3390/biom10010079
Chicago/Turabian StyleSatheesh, Noothan Jyothi, Samson Mathews Samuel, and Dietrich Büsselberg. 2020. "Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells" Biomolecules 10, no. 1: 79. https://doi.org/10.3390/biom10010079