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

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]