Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment
Abstract
:Simple Summary
Abstract
1. Introduction
2. VitC Is an Example of Repurposed Drugs with Anticancer Activity
3. VitC Targets Not Only Cancers but also the TME to Exert Anticancer Activity
3.1. VitC and Immune Microenvironment
3.2. VitC and Metabolic Microenvironment
3.3. VitC and Hypoxic Microenvironment
3.4. VitC and Acidic Microenvironment
3.5. VitC and Innerved Niche
3.6. VitC and Mechanical Microenvironment
3.7. VitC and Microbial Microenvironment
3.8. The Interplay between VitC and the Complicated Metastatic TME
4. Application of VitC as a Single Agent or Adjuvant to Target the TME
4.1. Monotherapy
4.2. Combination Therapy
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Category | Study Type(s) | VitC Dose and Administration | Main Mechanism | Findings | Reference | |
---|---|---|---|---|---|---|
cancer cells | Multiple cancers | cell line | 0–20 mM | pro-oxidant | Pharmacologic VitC selectively kills multiple cancer cells by initiating the production of extracellular H2O2 | [9] |
KRAS or BRAF mutant CRC | cell line and animal | 0–3 mM (in vitro); 4 g/kg, i.p. (in vivo) | pro-oxidant | DHA, the oxidized form of VitC, exhibits selective toxicity by elevating ROS to disrupt cancer cell metabolism | [10] | |
Breast cancer | cell line | 0–10 mM | pro-oxidant | VitC dose-dependently regulates the p66Shc/Rac1 pathway, which in turn induces apoptosis through ROS overexpression in cancer cells | [15] | |
Melanoma | cell line | 0–2 mM | DNA demethylation | Physiological concentrations of VitC inhibit melanoma migration and malignant transformation by increasing 5hmC levels without damaging normal melanocytes | [12] | |
Melanoma, Breast cancer | animal | 500 ppm pVitC, 150 mg/L VitC, oral | hydroxylase cofactor | Oral VitC promotes tumor collagen encapsulation and reduces MMP-9, IL-6, and VEGF levels, thereby inhibiting tumor growth and metastasis | [13] | |
VHL-deficient ccRCC | animal | 2 g/kg, i.p. | expression of HIF target genes is suppressed by enhanced TET2 activity | VitC inhibits HIF1/2α-mediated tumor metabolic reprogramming in a TET2-dependent manner, and increases the efficiency of glycolysis inhibitor (2-DG) to suppress ccRCC | [16] | |
TET2 and TP53 mutant Leukemia | cell line | 0–500 μM | DNA demethylation | VitC inhibits the proliferation of SKM-1 cells and promotes their differentiation to monocytes by restoring 5hmC levels | [17] | |
Leukemia | cell line and animal | 250 μM (in vitro); 4 g/kg, i.p. (in vivo) | DNA demethylation | VitC reverses aberrant AML self-renewal and promotes myeloid differentiation through the restoration of TET2 and TET3 | [11] | |
tumor stromal cells | T Lymphocytes | animal | 4 g/kg, i.p. | - | IVC promotes T cell differentiation, maturation, and immune memory formation, thereby increasing intra-tumor infiltration and immune responsiveness | [18] |
CD4+ Tregs cells | cell line and animal | 100 μg/mL (in vitro) | DNA demethylation | VitC was shown to enhance the expression and stability of Foxp3+ markers in a TET2/3-dependent manner during iTregs cell differentiation | [19] | |
γδ T cells | cell line | 0–200 μg/mL pVitC | DNA demethylation | The derivative pVitC regulates TGF-β-induced γδ T cell expansion and promotes conversion to Foxp3+ Tregs cells | [20] | |
γδ T cells | cell line | 12.5 μg/mL VitC, 50 μg/mL pVitC | - | High concentrations of VitC and pVitC promote restimulated Vγ9Vδ2 T cell expansion through an accelerated cell cycle and affect Th1/Th2 cytokine secretion | [21] | |
Th17 cells | cell line | 10 μg/mL | histone demethylation | In vitro, VitC reduces H3K9me3 levels and upregulates IL17 expression in a JMJD2-dependent manner | [22] | |
B cells | cell line and animal | 0–20 μM (in vitro); 4 g/kg, i.p. (in vivo) | DNA demethylation | VitC promotes B-cell differentiation and humoral immunity via enhancing the enzymatic activity of TET2/3 in vitro and in vivo | [23] | |
NK cells | cell line | 50 ng/mL | DNA demethylation | Low-dose VitC promotes KIR promoter demethylation and KIR expression, representing the maturation of NK cells | [24] | |
Monocytes | cell line | 0–500 μM | - | VitC induces alterations in monocyte surface markers, gene expression and protein secretion in a mimicked hypoxic microenvironment (1% O2) in vitro | [25] | |
Macrophages | cell line and animal | 0–4 mM (in vitro); 2 g/kg, 4 g/kg, i.p. (in vivo) | - | High-dose VitC induces apoptosis of M2 macrophages in TME and dose-dependently inhibits EMT and metastasis in ovarian cancer | [26] | |
Neutrophils | animal | 0.33 g/L, oral; 200 mg/kg, i.p. | multi-pathways | Oral VitC attenuates NETs formation and autophagic gene expression as well as inhibits NF-κB activation | [27] | |
Neutrophils | animal | 4 g/kg, oral | - | Oral high-dose VitC prevents melanoma invasion and increases neutrophil infiltration within the tumor | [28] | |
DCs | cell line and animal | 0–2 mM (in vitro); 0.08 mM vcDC (in vivo) | signal molecules modulation | VitC increases IL-12 and IFN-γ secretion from DC cells, which in turn drives Th1 immunity | [29] | |
Fibroblasts | cell line | 0–20 μM | - | VitC regulates the expression of genes related to ECM remodeling and cell adhesion, thereby affecting the phenotype of immortalized MEF | [30] | |
Endothelial cells | cell line | 0–200 μM | multi-pathways | VitC improves endothelial cell dysfunction through multiple molecules, involving NO, ROS, RNS, biopterins, and GSH | [31] | |
Neurons | cell line | 200 μM | signal molecules modulation | VitC oxidation induces necrotic apoptosis of neurons in a ROS-independent manner | [32] |
Combination Therapy | Study Type(s) | VitC Dose | Cancers (Cell Lines) | Target | Outcome(s) | Reference/NCT Number | |
---|---|---|---|---|---|---|---|
Immunotherapy | ICT (anti-PD-1, anti-CTLA-4) + VitC i.p. | animal | 4 g/kg | breast cancer (TS/A, 4T1), colorectal cancer (CT26, MC38), pancreatic cancer (PDAC), melanoma (B16-F10) | CD4+ and CD8+T lymphocytes, cancer cells | VitC increases the recruitment of lymphocytes in TME and improves the responsiveness of MMR-deficient tumors to ICT | [18] |
ICT (anti-PD-1) + VitC i.p. | cell line and animal | 1 mM (in vitro); 4 g/kg (in vivo) | B-cell lymphoma (A20, SU-DHL-6, OCI-Ly1, OCI-Ly7, OCI-Ly3) | CD8+T cells, macrophages, cancer cells | VitC synergistically increases ICT efficacy by enhancing retrovirus expression, CTLs infiltration, and IL12 production in lymphoma | [35] | |
ICT + IVC | cell line and animal | 250 μM (in vitro); 4 g/kg (in vivo) | melanoma (B16-OVA), leukemia (THP-1), colorectal cancer (MC38) | CD3+T cells, CTLs, CD56+NK cells, cancer cells | VitC upregulates TET-mediated cytokine expression to activate the IFN-γ/JAK2/STAT1 pathway, enhancing TILs infiltration, as well as ICT efficacy | [34] | |
ICT + VitC i.p. | cell line and animal | 0.5 g/kg | renal cell carcinoma (Renca, 786-O, A498) | CD4+ and CD8+T lymphocytes, cancer cells | VitC improves ICT efficacy via upregulation of cytokine and chemokine levels in a TET2-dependent manner, and indirectly induces PD-L1 expression | [86] | |
ICT + VitC | cell line | 0–50 μM | pancreatic cancer (PANC-1, BxPC-3 and MIA PaCa-2) | cancer cells | VitC inhibits histone acetyltransferase 1, which in turn downregulates PD-1 mRNA expression | [87] | |
ICD (oAds) + VitC i.p. | cell line and animal | 2 mM (in vitro); 4 g/kg (in vivo) | colon cancer (CT26), breast cancer (4T1), hepatocellular carcinoma (Hepa1-6) | DC cells, CD8+T cells, CD4+ T cells, CD3+T cells | High-dose VitC and oAds exhibit a synergistic antitumor effect, with increased CD8+ T cells and DCs and decreased M2-type TAM cells in TME | [77] | |
DC vaccines + VitC i.p. | cell line and animal | 0–2 mM (in vitro); 0.08 mM (in vivo) | melanoma (B16F10) | DC cells, CD8+T cells, CD4+ T cells | VitC promotes the secretion of co-cultured CD4+, CD8+ T cells in vitro and induces protective antitumor immunity in mice | [88] | |
Small-molecule kinase inhibitors | PI3K inhibitor (buparlisib) + oral VitC | cell line and animal | 0, 50, 100, 300 μM (in vitro); 3.3 g/L (animal) | TNBC (BT20, MDA-MB-453) | cancer cells | Synergistically, VitC enhanced KDM5-mediated histone H3K4 demethylation and boosted the efficacy of buparlisib | [89] |
sorafenib + IVC | cell line and clinical | 0–20 mM (in vitro); 75 g/infusion (clinical) | hepatocellular carcinoma (Hep G2, SNU-449, HuH-7), breast cancer (T47D), pancreatic cancer (MIA PaCa2) | cancer cells, angiogenesis | IVC and low-dose sorafenib exhibit synergistic cytotoxicity to suppress cancer viability and metastasis | [90] | |
erlotinib + gemcitabine + IVC | clinical, phase I | 50, 75, 100 g/infusion | pancreatic cancer | cancer cells, angiogenesis | IVC is well tolerated with erlotinib and gemcitabine in patients with advanced cancer | [91] | |
tyrosine kinase inhibitors (osimertinib or tarceva or iressa) + IVC | clinical, phase I/II | 30 g/infusion | EGFR mutant NSCLC | cancer cells | - | NCT03799094 | |
Monoclonal antibodies | bevacizumab+ Temozolomide + oral VitC | clinical, phase I | 250 mg/d | recurrent high-grade glioma | cancer cells, angiogenesis | - | NCT01891747 |
FOLFOXIRI +/- bevacizumab + IVC | clinical, phase III | 1.5 g/kg | peritoneal metastatic colorectal cancer | cancer cells, angiogenesis | - | NCT04516681 | |
mFOLFOX6 +/- bevacizumab + IVC | clinical, phase III | 1.5 g/kg | colorectal neoplasms | cancer cells, angiogenesis | - | NCT02969681 | |
cetuximab + VitC i.p. | cell line and animal | 1 mM, 2 mM (in vitro); 4 g/kg (animal) | colon cancer (RAS/BRAF wt, DiFi, CCK81, C75, IRCC-10A) | cancer cells, angiogenesis | Combination therapy delays the emergence of acquired drug resistance in EGFR mutant tumors in vitro and in vivo | [92] | |
Metabolic inhibitors | antibiotics (doxycycline, azithromycin) + VitC | cell line | 0–500 μM | breast cancer stem cells (MCF7) | cancer cell mitochondria | VitC and glycolysis inhibitor form a synthetic lethal strategy that targets both OXPHOS and glycolysis | [93,94] |
metformin + IVC | clinical, phrase II | 1.5 g/kg | hepatocellular carcinoma, pancreatic cancer, gastric cancer, colorectal cancer | cancer cell mitochondria and other targets | - | NCT04033107 | |
glycolysis inhibitors (3-PO) + VitC | cell line | 0–20 mM | NSCLC (H1299, H661, A549) | cancer cells | VitC synergizes with glycolysis inhibitors to induce apoptosis in NSCLC, mainly through the upregulation of ROS | [52] | |
Epigenetic therapies | DNMTis (5-aza-CdR) + VitC | cell line | 57 μM | colorectal cancer (HCT116), APL (HL60), breast cancer (MCF7), liver cancer (HepG2, SNU398) | cancer cells | In cooperation with DNMTis, low-dose VitC acts as a TET enzyme stimulator, which enhances viral mimicry response via endogenous retroviral gene transcription | [95] |
DNMTis (5-azacytidine) + oral VitC | clinical | 500 mg/d | AML, MDS, CMML | cancer cells | The treatment increased 5hmC/5mC levels in patients and upregulated retroviral gene expression in DNMTi naïve patients compared to the placebo group | NCT02877277; [76] | |
BETi + oral VitC | cell line and animal | 50–300 μM (in vitro); 3.3 g/L (in vivo) | TNBC (MDA-MB-231, BT-549, HCC1937), melanoma (A2058, SK-MEL28, SK-MEL2, C8161, 1205Lu) | cancer cells | Oral VitC and BETi collectively inhibit histone acetylation and improve tumor response to BETi treatment in vitro and in vivo. The underlying molecular mechanisms involve disruption of BRD4 and H4 interactions and upregulation of HDAC1 expression | [96,97] | |
Diet therapy | ketogenic diet + IVC | clinical | 15–40 g/d | multiple cancers | cancer cells | VitC controls the inflammatory status of patients with advanced cancer, as well as increases ketone body content after a ketogenic diet | [98] |
fasting-mimicking + IVC | cell line and animal | 350 μM (in vitro); 4 g/kg (in vivo) | KRAS mutant cancers: colorectal cancer (HCT116, DLD-1, CT26), lung cancer (H23, H727), pancreatic cancer (PANC1) | cancer cells | VitC and fasting-mimicking synergistically disrupt ROS and iron metabolism to enhance toxicity to KRAS-mutated tumor cells, sensitizing oxaliplatin therapy | [99] | |
very low carbohydrate diet + IVC | clinical, phase I/II | 25, 50, 75, 100 g/infusion | KRAS and BRAF mutant colon cancer stage IV | cancer cells | - | NCT04035096 |
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Li, W.-N.; Zhang, S.-J.; Feng, J.-Q.; Jin, W.-L. Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment. Cancers 2022, 14, 2608. https://doi.org/10.3390/cancers14112608
Li W-N, Zhang S-J, Feng J-Q, Jin W-L. Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment. Cancers. 2022; 14(11):2608. https://doi.org/10.3390/cancers14112608
Chicago/Turabian StyleLi, Wen-Ning, Shi-Jiao Zhang, Jia-Qing Feng, and Wei-Lin Jin. 2022. "Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment" Cancers 14, no. 11: 2608. https://doi.org/10.3390/cancers14112608
APA StyleLi, W. -N., Zhang, S. -J., Feng, J. -Q., & Jin, W. -L. (2022). Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment. Cancers, 14(11), 2608. https://doi.org/10.3390/cancers14112608