Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH^-)

Abstract

Rationale: Ascorbate is an essential micronutrient known for redox functions at normal physiologic concentrations. In recent decades, pharmacological ascorbate has been found to selectively kill tumour cells. However, the dosing frequency of pharmacologic ascorbate in humans has not yet been defined.Methods: We determined that among five hepatic cell lines, Huh-7 cells were the most sensitive to ascorbate. The effects of high-dose ascorbate on hepatoma were therefore assessed using Huh-7 cells and xenograft tumour mouse model.Results: In Huh-7 cells, ascorbate induced a significant increase in the percentage of cells in the G0/G1 phase, apoptosis and intracellular levels of ROS. High doses of ascorbate (4.0 pmol cell-1), but not low doses of ascorbate (1.0 pmol cell-1), also served as a pro-drug that killed hepatoma cells by altering mitochondrial respiration. Furthermore, in a Huh-7 cell xenograft tumour mouse model, intraperitoneal injection of ascorbate (4.0 g/kg/3 days) but not a lower dose of ascorbate (2.0 g/kg/3 days) significantly inhibited tumour growth. Gene array analysis of HCC tumour tissue from xenograft mice given IP ascorbate (4.0 g/kg/3 days) identified changes in the transcript levels of 192 genes/ncRNAs involved in insulin receptor signalling, metabolism and mitochondrial respiration. Consistent with the array data, gene expression levels of AGER, DGKK, ASB2, TCP10L2, Lnc-ALCAM-3, and Lnc-TGFBR2-1 were increased 2.05-11.35 fold in HCC tumour tissue samples from mice treated with high-dose ascorbate, and IHC staining analysis also verified that AGER/RAGE and DGKK proteins were up-regulated, which implied that AGER/RAGE and DGKK activation might be related to oxidative stress, leading to hepatoma cell death.Conclusions: Our studies identified multiple mechanisms are responsible for the anti-tumour activity of ascorbate and suggest high doses of ascorbate with less frequency will act as a novel therapeutic agent for liver cancer in vivo.

Identification of Specific Long Non-Coding Ribonucleic Acid Signatures and Regulatory Networks in Prostate Cancer in Fine-Needle Aspiration Biopsies

“…After washing with PBST, the blots were treated with a horseradish peroxidase (HRP) conjugated anti-rabbit IgG. Detection of blots was performed using Meilunbio ® fg super sensitive ECL luminescence reagent (Dalian Meilun Biotechnology Co., Ltd.) (Zhang et al, 2019).…”

Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxic KRAS mutant colon cancer

“…More recently, it has also been described that Vitamin C is capable to kill hepatic cell lines and BRAF mutated thyroid cancer cells with high efficacy 19 , 20 .…”

γ-Cyclodextrin Metal-Organic Framework as a Carrier to Deliver Triptolide for the Treatment of Hepatocellular Carcinoma

“…The cell uptake of C6@CD-MOF by Caco-2 cells was evaluated by a Leica TCS-SP8 confocal laser scanning microscopy (CLSM) (Wetzlar, Germany). 1 mL Caco-2 cells were seeded into confocal dishes at the density of 5 × 10 4 •mL − 1 12 h prior to the experiment. Then the culture medium was removed and the cells were washed twice with PBS and incubated with free C6 or C6@CD-MOF solution for 2 h. Thereafter, the cells were rinsed three times with PBS and xed with 4% paraformaldehyde.…”