Table 1.
Combinations of anti-cancer agents and high-dose VitC in pre-clinical in vitro and in vivo studies
| Combination Treatment(s) | Type Drug | Cancer type(s) | Type of Study | Sample Size | Dose In vitro | Tx duration | Dose, Administration In vivo | Schedule In vivo | Results | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|
| 2Gy | Radiotherapy | Pancreatic | In vitro | n = 1 cell line | 4 mM | 24 h | – | – | Radio-sensitizing | [87] |
| 5-FU | Chemotherapy | Colorectal | In vitro, In vivo | n = 3 cell lines, n = 48 Balb/c nu/nu mice | 0.15–13.3 mM | 24, 48, 72, 96 h | 150 mg/kg IP | Daily | In vitro synergy, in vivo no benefit | [88] |
| Gastric | In vitro, In vivo | n = 2 cell lines, n = 60 athymic-nu/nu mice | 1 mM | 1 h | 4 g/kg IP | Daily (20–30 days) | Enhanced efficacy | [89] | ||
| Anti-PD-1 | Immunotherapy | B cell lymphoma | In vivo | n = 40 immunocompetent syngenic BALB/c mice | – | N/S | 1500 mM IP | Daily (dose-escalated, 10-19 days) | Synergy | [90] |
| Anti-PD-1/Anti-CTL-4 | Immunotherapy | Breast, Colorectal, Pancreatic | In vivo | n = 13 immunocompetent syngeneic mice | – | N/S | 4 g/kg IP | Daily 5x/week | Synergy and effective antitumor immune memory | [91] |
| ATO | Chemotherapy | Colorectal | In vitro | n = 2 cell lines | 2 mM | 24 h | – | – | Synergy | [92] |
| Colorectal, Pancreatic (mKRAS) | In vitro, In vivo | n = 7 cell lines, n = 30 mice | 1 mM | 48, 72 h | 1.5 g/kg IV | Daily | Enhanced efficacy | [93] | ||
| AML and APL | In vitro | n = 5 cell lines, n = 48 primary cells | 3 mM | 72 h | – | – | Enhanced efficacy | [94] | ||
| CLL | In vitro | Primary cells of n = 18 patients | 1 mM | 24, 72 h | – | – | Enhanced efficacy | [95] | ||
| ATO + vitE | Chemotherapy | APL | In vitro | n = 1 cell line | 0.1 mM | 48 h | – | – | Synergy | [96] |
| Auranofin | Anti-inflammatory | Triple-Negative Breast | In vitro, In vivo | n = 5 cell lines, n = 25 swiss Nude Mice | 2.5 mM | 24 h | 4 g/kg IP | Daily (15 days) | Synergy | [97] |
| Azacytidine | Chemotherapy | Colorectal | In vitro | n = 1 cell line | 0.01, 0.05 mM | 72 h | – | – | Synergy | [98] |
| Carboplatin | Chemotherapy | Gastric | In vitro, In vivo | n = 2 cell line, n = 60 athymic-nu/nu mice | 1 mM | 1 h | 4 g/kg IP | Daily (20–30 days) | Enhanced efficacy | [89] |
| Cetuximab | Targeted therapy | Colorectal (mKRAS) | In vitro, In vivo | n = 5 cell lines, n = N/S athymic nude mice | 0.3, 0.5, 0.7 mM | 6 h | 0.5 g/kg IP | Daily (14 days) | Synergy and abrogates resistance via SVCT-2 | [99] |
| Cisplatin | Chemotherapy | Gastric | In vitro | n = 1 cell line | 0.000284, 0.000568 mM | 48 h | – | – | Synergy | [100] |
| Cervical | In vitro | n = 2 cell lines | 0.000568 mM | 24, 48, 72 h | – | – | Synergy | [101] | ||
| Oral squamous | In vitro, In vivo | n = 8 cell lines, n = 24 C57BL/6 mice | 0.125, 0.25, 0.5, 1 mM | 72 h | 4 g/kg IP | Daily (21 days) | Synergy | [51] | ||
| Ovarian | In vitro | n = 1 cell line | 2 mM | 2 h | – | – | Enhanced efficacy | [102] | ||
| Cervical | In vitro | n = 2 cell lines | 1, 2.5, 3.3, 16 mM | 24, 48, 72 h | – | – | Synergy | [103] | ||
| Gastric | In vitro, In vivo | n = 2 cell lines, n = 60 athymic-nu/nu mice | 1 mM | 1 h | 4 g/kg IP | Daily (20–30 days) | Enhanced efficacy | [89] | ||
| CPI-613 | Targeted therapy | CLL | In vitro | n = 2 cell lines | 0.1–2 mM | 24 h | – | – | Synergy | [104] |
| Decitabine | Chemotherapy | AML | In vitro | n = 2 cell lines | 0.3 mM | 24, 48, 72 h | – | – | Synergy | [105] |
| Colorectal | In vitro | n = 1 cells line | 0.01, 0.05 mM | 72 h | – | – | Synergy | [98] | ||
| Doxorubicin | Chemotherapy | Cervical | In vitro | n = 2 cell lines | 1, 2.5, 3.3, 16 mM | 24, 48, 72 h | – | – | Synergy | [103] |
| Doxycycline | Targeted therapy | Cancer Stem Cells | In vitro | n = 1 cells line | 0.25–0.5 mM | 5 days | – | – | Synergy | [106] |
| Doxycycline + Azithromycin | Targeted therapy | Cancer Stem Cells | In vitro | n = 1 cell line | 0.25 mM | 5 days | – | – | Synergy | [107] |
| Eribulin mesylate | Chemotherapy | Breast | In vitro | n = 6 cell lines | 5, 10, 20 mM | 2 h (×1 or ×2) | – | – | Enhanced efficacy | [108] |
| Etoposide | Chemotherapy | Glioblastoma | In vitro | n = 1 cell line | 1 mM | 48, 96, 144 h | – | – | Enhanced efficacy | [54] |
| Fulvestrant | Hormonal therapy | Breast | In vitro | n = 6 cell lines | 5, 10, 20 mM | 2 h (×1 or ×2) | – | – | Enhanced efficacy | [108] |
| Gefitinib | Targeted therapy | Non-small cell Lung | In vitro | n = 3 cell lines | 0.5, 1, 2.5, 5, 10 mM | 1 h | – | – | Synergy | [109] |
| Gemcitabine | Chemotherapy | Pancreatic | In vitro, In vivo | n = 6 cell lines, n = N/S athymic nude mice | 0.001 mM | 1 h | 4 g/kg IP | Twice daily (6 days) | Radioprotection and radiosensitization | [110] |
| Pancreatic | In vivo | n = 32 mice | – | – | 4 g/kg IP | Daily (45 days) | Enhanced efficacy and VitC equal to combination | [14] | ||
| Gemcitabine + Ionizing radiation (IR) | Chemoradiotherapy | Sarcoma | In vitro, In vivo | n = 2 cell lines, n ≥ 7 per treatment group, athymic-nu/nu mice | 2, 5 mM | 1 h | 4 g/kg IP | Daily (40-60 days) | Radio-chemo sensitizer | [111] |
| Ibrutinib | Targeted therapy | CLL | In vitro | n = 2 cell lines, n = 6 primary cells | 0.1–2 mM | 24 h | – | – | Synergy | [104] |
| Idelalisib | Targeted therapy | CLL | In vitro | n = 2 cell lines, primary cells of n = 6 patients | 0.1–2 mM | 24 h | – | – | Synergy | [104] |
| Irinotecan | Chemotherapy | Colorectal | In vitro, In vivo | n = 3 cell lines, n = 48 Balb/c nu/nu mice | 0.15–13.3 mM | 24, 48, 72, 96 h | 150 mg/kg IP | Daily | Synergy in vitro, enhanced efficacy in vivo | [88] |
| Gastric | In vitro, In vivo | n = 2 cell lines, n = 60 athymic-nu/nu mice | 1 mM | 1 h | 4 g/kg IP | Daily (20–30 days) | Enhanced efficacy | [89] | ||
| Gastric | In vitro, In vivo | n = 5 cell lines, n = 24 ALB/c nude mice | 2, 4 mM | 2 h | 4 g/kg IP | Twice daily | Synergy | [112] | ||
| Melphalan | Chemotherapy | Multiple Myeloma | In vitro, In vivo | Primary cells of n = 13 patients, n = 45 NOD.Cγ-Rag1 mice | 8, 20 mM | 1 h | 4 mg/kg IP | Daily | Synergy | [113] |
| Metformin | Multitargeted Therapy | CLL | In vitro | n = 2 cell lines | 0.1–2 mM | 24 h | – | – | Synergy | [104] |
| Olaparib (PARP inhibitor) | Targeted therapy | AML (TET2-deficient) | In vitro | n = 6 cell lines | 0.125, 0.25, 0.5, 1 mM | 72 h | – | – | Enhanced sensitivity | [22] |
| Oligomycin A | Targeted therapy | CLL | In vitro | n = 2 cell lines | 0.1–2 mM | 24 h | – | – | Synergy | [104] |
| Oxaliplatin | Chemotherapy | Colorectal | In vitro, In vivo | n = 3 cell lines, n = 48 (6 × 8) Balb/c nu/nu mice | 0.15–13.3 mM | 24, 48, 72, 96 h | 150 mg/kg IP | Daily | Synergy in vitro, enhanced efficacy in vivo | [88] |
| Gastric | In vitro, In vivo | n = 5 cell lines, n = 24 ALB/c nude mice | 2, 4 mM | 2 h | 4 g/kg IP | Twice daily | Synergy in vitro, enhanced efficacy in vivo | [112] | ||
| Oxaliplatin + Fasting mimicking diet (FMD) | Chemotherapy + Fasting | Colorectal, Pancreatic, Lung (mKRAS); Prostate, Ovarian | In vitro, In vivo | n = 11 cell lines, n = 38 NSG and BALB/c mice | ≥0.3 mM | 24 h | 4 g/kg IP | Twice daily (36 days) | Synergy | [114] |
| Paclitaxel | Chemotherapy | Oral squamous | In vivo | n = 96 Swiss albino mice | – | N/S | 10 mg oral | – | Enhanced efficacy | [115] |
| Gastric | In vitro, In vivo | n = 2 cell lines, n = 60 athymic-nu/nu mice | 1 mM | 1 h | 4 g/kg IP | Daily (20–30 days) | Enhanced efficacy | [89] | ||
| PLX4032 | Targeted therapy | Thyroid | In vitro, In vivo | n = 3 cell lines; n = 20 nude mice | 0.1–2 mM | 72 h | 3 g/kg IP | Daily (15 days) | Synergy | [64] |
| Sorafenib | Targeted therapy | Liver | In vitro | n = 5 cell lines | 2.5, 5, 7.5, 10, 20 mM | 2 h | – | – | Synergy | [116] |
| Sulfasalazine | Anti-inflammatory | Prostate | In vitro, In vivo | n = 2 cell lines, n = ~ 24 BALB/c nude mice | 1, 2 mM | 2-48 h | 4 g/kg IP | Twice daily (16 days) | Synergy | [117] |
| Sulindac | Anti-inflammatory | Colorectal | In vitro | n = 2 cell lines | 0.5 mM | 48 h | – | – | Synergy | [118] |
| Tamoxifen | Hormonal therapy | Breast | In vitro | n = 6 cell lines | 5, 10, 20 mM | 2 h (×1 or ×2) | – | – | Enhanced efficacy | [108] |
| Temozolomide | Chemotherapy | Glioblastoma | In vitro | n = 1 cell line | 1 mM | 48, 96, 144 h | – | – | Enhanced efficacy | [54] |
| Thieno-triazolo-1,4-diazepine (JQ1) | Targeted therapy | Melanoma | In vitro, In vivo | n = 5 cell lines; n = 10 Gulo−/− and 10 Gulo+/+ mice | 0.00005–0.0001 mM | 72 h | 3.3 g/L and 0.33 g/L, oral | Daily (14 days) | Enhanced efficacy | [119] |
| TMZ/carboplatin + IR | Chemoradiotherapy | Glioblastoma, Non-small cell Lung | In vitro, In vivo | n = 12 cell lines, n = ~ 42 athymic nude mice | 1, 2 mM | 1 h | 4 g/kg IP | Daily | Radio-chemo sensitizer | [16] |
| Topotecan | Chemotherapy | Breast | In vitro | n = 1 cell line | 1 mM | 48 h | – | – | Synergy | [120] |
| TPP derivative dodecyl-TPP (d-TPP) | Targeted therapy | Cancer Stem Cells | In vitro | n = 2 cell lines | 0.25–0.5 mM | 5 days | – | – | Synergy | [121] |
| Trastuzumab | Targeted therapy | Breast | In vitro | n = 6 cell lines | 5, 10, 20 mM | 2 h (×1 or ×2) | – | – | Enhanced efficacy | [108] |
| Triethylenetetramine (TETA) | Targeted therapy | Breast | In vitro, In vivo | n = 9 cell lines, n = 40 BALB/c-nu | 1 mM | 12, 24 h | 3 g/kg IP | Daily (25 days) | Synergy | [122] |
| Vemurafenib | Targeted therapy | BRAF mutant Melanoma | In vitro, In vivo | n = 2 cell lines, n = 18 C57BL/6 mice | 1, 5 mM | 48 h | 0.03 mg/kg oral | Daily | Synergy and abrogates resistance | [123] |
| Venetoclax | Targeted therapy | CLL | In vitro | n = 2 cell lines, primary cells of n = 6 patients | 0.1–2 mM | 24 h | – | – | Synergy | [104] |
| Vit K3 (Menadione) + Everolimus or Barasertib | Vitamin + Targeted therapy | ALL | In vitro | n = 1 cell line | 0.3 mM | 24, 72 h | – | – | Synergy | [124] |
A total of 47 combinations in 44 pre-clinical studies from 2016 to 2021 were retrieved from PubMed using search terms (vitamin c OR ascorbate OR ascorbic acid) AND (combination OR synergy OR combined) AND (cancer)
Tx treatment, mM millimolar, IP intraperitoneal, IV intravenous, JQ1 Thieno-triazolo-1,4-diazepine, 5-FU 5-fluorouracil, Vit vitamin, IR irradiation, TMZ temozolomide, Gem gemcitabine, Dox Doxycycline, Oxa oxaplatin, TETA Triethylenetetramine, BRAF v-raf murine sarcoma viral oncogene homolog B1, PARP poly (ADP-ribose) polymerase, d-TPP TPP derivative dodecyl-TPP, ATO arsenic trioxide, 3-PO 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one, CLL chronic lymphocytic leukemia, AML acute myeloid leukemia, APL acute promyelocytic leukemia, ALL acute lymphoblastic leukemia, TET ten eleven translocation