Table 2.
Preclinical and clinical evidence for different doses of VitC as a novel therapeutic adjuvant.
| 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 | |
Abbreviations: i.p., intraperitoneal injection; IVC, intravenous vitamin C; ICT, immune checkpoint therapy; PD-1, programmed death-1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; ICD, immunogenic cell death; oAds, oncolytic adenoviruses; PI3K, phosphoinositide 3-kinase; FOLFOXIRI, (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan); mFOLFOX6, (5-fluorouracil, leucovorin, oxaliplatin); 3-PO, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; DNMTis, DNA methyltransferase inhibitors; 5-aza-CdR, 5-aza-2′-deoxycytidine; BETi, bromodomain and extra-terminal domain inhibitors; NSCLC, non-small cell lung cancer; APL, acute promyelocytic leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; CMML, chronic myelomonocytic leukemia; TNBC, triple negative breast cancer; TILs, tumor-infiltrating lymphocytes; CTLs, cytotoxic T lymphocyte.