Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue

Kuiper, Caroline; Vissers, Margreet C.M.; Hicks, Kevin O.

doi:10.1016/j.freeradbiomed.2014.09.023

Cited by 41 publications

(54 citation statements)

References 49 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, our data shows that ascorbate can be retained for longer in tumours compared to plasma and liver. Using our previously reported diffusion parameters [34], we suggest that ascorbate stabilization in a hypoxic environment could be responsible for its persistence within tumours. We speculate that the tumour tissue behaves as a unique peripheral compartment, and that the slower elimination of ascorbate may allow for increased interaction with tumour tissue.…”

Section: Discussionmentioning

confidence: 85%

“…Tumour ascorbate concentrations were simulated using an in vitro 3D cellular model which incorporates active cellular ascorbate uptake and transport [34].…”

Section: Pharmacokinetic Parametersmentioning

confidence: 99%

“…To investigate the factors governing the retention of ascorbate content in the tumour relative to liver tissue and plasma, we compared the ascorbate concentration data with predicted pharmacokinetics, obtained using estimates of tissue permeability, extravascular transport and cell uptake parameters established previously in a 3D cellular system in which we modelled the concentration-time-distance profile of ascorbate over a linear (400 mm) inter-capillary distance [34].…”

Section: Modelling the Extravascular Transport Of Ascorbate In Tumoursmentioning

confidence: 99%

“…Pharmacokinetic studies in humans have demonstrated that the uptake of ascorbate following oral ingestion is tightly regulated [32,33], and that the bioavailability is increased by 70-fold when administered intravenously [7,33,14]. We have previously proposed that these supra-physiological plasma concentrations could allow ascorbate to overcome the diffusion barrier of poorly-perfused solid tumours [34], thereby boosting intracellular levels. To date, however, no study has monitored the pharmacokinetics of ascorbate uptake into tumour tissue following high dose ascorbate (high-dose vitamin C, HDVC) administration.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice

Campbell

Vissers

Wohlrab

et al. 2016

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 85%

“…Tumour ascorbate concentrations were simulated using an in vitro 3D cellular model which incorporates active cellular ascorbate uptake and transport [34].…”

Section: Pharmacokinetic Parametersmentioning

confidence: 99%

Section: Modelling the Extravascular Transport Of Ascorbate In Tumoursmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice

Campbell

Vissers

Wohlrab

et al. 2016

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

“…The authors concluded that supraphysiological ascorbate levels (only achieved by i.v. administration) may overcome the diffusion barrier in tumors [15]; however, it remains to be determined which ascorbate concentration can be achieved in malignant tumors and their metastases in human cancer patients.…”

Section: Historical Backgroundmentioning

confidence: 99%

Molecular mechanisms of pharmacological doses of ascorbate on cancer cells

Venturelli

Sinnberg

Niessner

et al. 2015

Wien Med Wochenschr

View full text Add to dashboard Cite

Intravenous application of high-dose ascorbate (vitamin C) has been used in complementary medicine since the 1970s to treat cancer patients. In recent years it became evident that high-dose ascorbate in the millimolar range bears selective cytotoxic effects on cancer cells in vitro and in vivo. This anticancer effect is dose dependent, catalyzed by serum components and mediated by reactive oxygen species and ascorbyl radicals, making ascorbate a pro-oxidative pro-drug that catalyzes hydrogen peroxide production in tissues instead of acting as a radical scavenger. It further depends on HIF-1 signaling and oxygen pressure, and shows a strong epigenetic signature (alteration of DNA-methylation and induction of tumor-suppressing microRNAs in cancer cells). The detailed understanding of ascorbate-induced antiproliferative molecular mechanisms warrants in-depth preclinical evaluation in cancer-bearing animal models for the optimization of an efficacious therapy regimen (e.g., combination with hyperbaric oxygen or O2-sensitizers) that subsequently need to be evaluated in clinical trials.

show abstract

Role of Sodium‐Dependent Vitamin C Transporter‐2 and Ascorbate in Regulating the Hypoxic Pathway in Cultured Glioblastoma Cells

Burgess,

Praditi,

Phillips

et al. 2024

J of Cellular Biochemistry

View full text Add to dashboard Cite

The most common and aggressive brain cancer, glioblastoma, is characterized by hypoxia and poor survival. The pro‐tumour transcription factor, hypoxia‐inducible factor (HIF), is regulated via HIF‐hydroxylases that require ascorbate as cofactor. Decreased HIF‐hydroxylase activity triggers the hypoxic pathway driving cancer progression. Tissue ascorbate accumulates via the sodium‐dependent vitamin C transporter‐2 (SVCT2). We hypothesize that glioblastoma cells rely on SVCT2 for ascorbate accumulation, and that knockout of this transporter would disrupt the regulation of the hypoxic pathway by ascorbate. Ascorbate uptake was measured in glioblastoma cell lines (U87MG, U251MG, T98G) by high‐performance liquid chromatography. CRISPR/Cas9 was used to knockout SVCT2. Cells were treated with cobalt chloride, desferrioxamine or 5% oxygen, with/without ascorbate, and key hypoxic pathway proteins were measured using Western blot analysis. Ascorbate uptake was cell line dependent, ranging from 1.7 to 11.0 nmol/106 cells. SVCT2‐knockout cells accumulated 90%–95% less intracellular ascorbate than parental cells. The hypoxic pathway was induced by all three stimuli, and ascorbate reduced this induction. In the SVCT2‐knockout cells, ascorbate had limited effect on the hypoxic pathway. This study verifies that intracellular ascorbate is required to suppress the hypoxic pathway. As patient survival is related to an activated hypoxic pathway, increasing intra‐tumoral ascorbate may be of clinical interest.

show abstract

Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue

Cited by 41 publications

References 49 publications

Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice

Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice

Molecular mechanisms of pharmacological doses of ascorbate on cancer cells

Role of Sodium‐Dependent Vitamin C Transporter‐2 and Ascorbate in Regulating the Hypoxic Pathway in Cultured Glioblastoma Cells

Contact Info

Product

Resources

About