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Table 1 Combinations of anti-cancer agents and high-dose VitC in pre-clinical in vitro and in vivo studies

From: High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer

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]
  1. 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)
  2. 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