Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2... - 0 views
www.nature.com/...s41698-017-0044-8
cancer cancer stem cells liver cancer vitamin C IV vitamin C oncology
shared by Nathan Goodyear on 30 Jan 18
- No Cached
-
Chen et al. have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.
-
Ascorbic acid (the reduced form of vitamin C) is specifically transported into cells by sodium-dependent vitamin C transporters (SVCTs)
-
SVCT-1 is predominantly expressed in epithelial tissues
- ...41 more annotations...
-
whereas the expression of SVCT-2 is ubiquitous
-
differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.
-
high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.
-
Hepatocellular carcinoma (HCC)
-
The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells
-
DNA double-strand damage was found following VC treatment
-
DNA damage was prevented by NAC
-
Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight
-
Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs
-
VC is one of the numerous common hepatoprotectants.
-
Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells
-
we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.
-
Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients
-
Median DFS time for VC users was 25.2 vs. 18 months for VC non-users
-
intravenous VC use is linked to improved DFS in HCC patients.
-
In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo
-
the authors here made similar mistakes to the Mayo authors i.e. under doses here in this study. They dosed at only 2 grams IVC. A woefully low dose of IVC.
-
-
Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.
-
-
Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy
-
As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity
-
we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs
-
SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC
-
CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance
-
we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death
-
as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs
-
In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells
-
we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo
-
Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation
-
so, exclude the benefit to patients until the exact mechanism of action, which will never be fully elicited?!?!?
-
-
Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy
-
Terribly inadequate dose. Target is 20-40 mM which other studies have found occur with 50-75 grams of IVC.
-
-
several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS
-
high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo
-
high recurrence rate and heterogeneity
-
tumor progression, metastasis, and chemotherapy-resistance
-
SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues
-
high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior
-
SVCT-2 is enriched in liver CSCs
-
these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.
-
pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration
-
The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner
-
VC and cisplatin combination further caused cell apoptosis in tumor xenograft
-
These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response
-
qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs
-
IV vitamin C in vitro and in vivo found to "preferentially" eradicate cancer stem cells. In addition, IV vitamin C was found to be adjunctive to chemotherapy, found to be hepatoprotectant. This study also looked at SVCT-2, which is the transport protein important in liver C uptake.