Article points to potential chemosensitizing effect of T3 in cancer treatment. Chemotherapy with increased metabolic demand with T3 may improve cancer kill rate.
pharmacological concentrations of AA can sensitize cancer cells to chemotherapy, enhancing its antineoplastic effect
synergistic effect with conventional chemotherapeutic drugs is a fact already reported, in various types of cancer, by numerous authors, namely in pancreatic (Espey et al., 2011), prostate (Gilloteaux et al., 2014), lung (Lee et al., 2017), breast (Kurbacher et al., 1996; Wu et al., 2017) and ovarian (Ma et al., 2014) cancers.
chemosensitizing effect of vitamin C has already been proven by several authors in various types of cancer
intravenous pharmacological concentrations, may not only potentiate the effects of conventional chemotherapy, but also improve the quality of life of cancer patients
AA reinforced the anti-proliferative activity of 5-FU
Combined treatment induced a reduction of 11.5% and 43% in cell viability compared with AA or Iri therapies, respectively, emphasizing the synergistic effect
cytotoxic effect occurred with treatment with Iri alone, but also this effect was further potentiated by the presence of AA.
association of AA with Oxa showed very promising results, considering that a synergistic effect was demonstrated, in almost all conditions
AA and Oxa seem to act synergistically by the activation of the intrinsic pathway of apoptosis, translated on the statistically significant increase of the ratio between BAX and BCL-2 proteins, which in turn is associated with a decrease of Δψm
High CBD downregulates prostate CBD1, CBD2, chemosensitizes CSCs, suppressed cancer cell formation, down regulated IL-6 and IL-8, decreased PSA, and VEGF.
IV vitamin C shown to augment cancer killer effect of chemotherapy. This study looked at ovarian cancer in animal models and in humans. The effect--a synergistic effect was found that promoted tumor destruction. The great thing about IV vitamin C is the benefit but also the very low side effect profile.
the mortality rate of EOC has not been significantly changed for several decades
Sequencing revealed that almost all tumors (96%) had mutations in TP53, which serves as a major driver of this cancer
Low-prevalence but statistically significant mutations in nine other genes including NF1, BRCA1, BRCA2, RB1, and CDK12 were also identified, but the majority of genes were mutated at low frequency, making it difficult to distinguish between driver and passenger mutations
KPNB1 inhibition via any of three KPNB1 siRNAs or importazole treatment induced apoptosis in human EOC cell lines (Fig. 3 A–F and Fig. S4), and was accompanied by an increase in the expression levels of the proapoptotic proteins BAX and cleaved caspase-3
Stable overexpression of KPNB1 in SKOV3 and OVCAR3 (Fig. S6) significantly accelerated cell proliferation/survival (Fig. 5 A–C), confirming that KPNB1 functions as an oncogene in EOC
KPNB1 overexpression significantly decreased caspase-3/7 activity (Fig. 5D), in addition to the expression levels of cleaved caspase-3 and BAX proteins (Fig. 5E). KPNB1 overexpression also decreased p21 and p27 protein levels (Fig. 5E), as opposed to their increase by KPNB1 inhibition
KPNB1 functions as an antiapoptotic and proproliferative oncogene in EOC.
Patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1
KPNB1 acts as an oncogene in human EOC and represents a promising therapeutic target.
ivermectin treatment suppressed cell proliferation/viability in a dose-dependent manner (Fig. 7A), indicating that it exerts an antitumor effect on EOC
ivermectin also induced apoptosis
ivermectin increased the expression levels of BAX, and cleaved PARP, as well as p21 and p27
KPNB1 inhibition is responsible for the antitumor effect of ivermectin
we found that ivermectin synergistically reduced cell proliferation/viability in combination with paclitaxel in human EOC cells
Single treatment of ivermectin or paclitaxel reduced tumor growth in nude mice, but, notably, combination treatment of ivermectin and paclitaxel almost completely suppressed tumor growth
ERBB2, is amplified and overexpressed in many cancers, including breast (31), ovary (31), colon (32), bladder (33), non-small-cell lung (34), and gastric cancer (35), and is a poor prognostic factor in certain cancer types
KPNB1 was the second-highest-ranked gene identified in our screen
Increased KPNB1 protein levels have been reported in several cancers, including cervical cancer (42), hepatocellular carcinoma (43), and glioma (44), suggesting KPNB1’s oncogenic potential in these tumor types
our findings suggest that KPNB1 might serve as a master regulator of cell cycle by regulating several cell cycle-related proteins, including p21, p27, and APC/C family members
higher and/or more-frequent doses of ivermectin than currently approved for humans are well tolerated in humans
none of the mice in this study treated with the effective dosage of ivermectin for in vivo anticancer therapy showed severe adverse event
we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC cell lines than either drug alone
Ivermectin found to be pro-apoptotic for the epithelial ovarian cancer oncogene, KPNB1 in in Vivo study. This effective anti-parasitic drug inhibits the KPNB1 oncogene.
Proof of conept finds IV vitamin C is synergistic with chemotherapy in ovarian cancer. In addition, a reduction in toxic side effects were also seen. Why is vitamin C not used??? The results were found in in vivo and in vitro study.
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
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.
Their comfort zone was 1mM. They should have targeted 20-40 mM.
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
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.
Vitamin C alone at concentrations up to 57 μM had little effect on cell growth but was toxic at 228 μM (SI Appendix, Fig. S1B), in line with recent studies of high vitamin C concentrations (125–2,000 μM)
In our combination approach, vitamin C increased the effects of low doses of 5-aza-CdR, with 57 μM vitamin C almost doubling the growth inhibition
Using the Chou–Talalay method (28), we found that the two compounds indeed acted synergistically, rather than additively, to inhibit cancer cell growth over the physiological ranges of vitamin C in healthy individuals (26–84 μM)
These results show that targeting the cancer DNA methylome by combining low-dose 5-aza-CdR and vitamin C stimulates the expression of ERVs, the induction of a cell-autonomous immune activation response, and increased apoptosis of cancer cells
The addition of vitamin C to treatment protocols therefore may be a straightforward way to increase the clinical efficacy of such drugs in MDS and leukemia patients
Vitamin C deficiency has been seen previously in patients with multiple types of cancer, including hematological malignancies (35⇓–37). We predict that these patients might receive the most benefits from the combination treatment.
induction of an innate immune response
We therefore measured plasma concentrations of vitamin C in a small number of patients with miscellaneous hematologic malignancies. Strikingly, 58% of patients with hematological neoplasia who were not taking vitamin C supplements had severe vitamin C deficiency (serum concentration <11.4 μM, at which clinical features of scurvy may be manifested) (34), and 33% had vitamin C levels below the normal range
it is possible that vitamin C was oxidized to DHA before it was transported into the cells
Oral administration of vitamin C should be sufficient for the therapeutic strategy, because the concentrations reported in this study would not require i.v. administration.
This statement lacks a basic understanding of vitamin C pharmacokinetics.
Vitamin C is an essential nutrient for humans and has been reported to increase IFN levels in human cells upon virus infection
daily treatment with vitamin C alone at physiological concentrations enhanced the expression of viral-defense genes relative to untreated cells
When combined with low-dose 5-aza-CdR, physiological concentrations of vitamin C synergistically inhibited cancer-cell growth and induced apoptosis. Such synergy was associated with increased ERV expression and dsRNA in treated cells. The mechanism of action differs from that of vitamin C at higher doses, which involves its pro-oxidant activity, including GSH inhibition, to generate reactive oxygen species
This activity has been shown to induce DNA damage and to enhance the sensitivities of myeloid malignancies, multiple myeloma, and cutaneous T-cell lymphoma to arsenic trioxide (41⇓⇓–44). It also can increase chemosensitivity of ovarian cancer cells (27) and selectively kill KRAS or BRAF mutant colorectal cancer cells by inhibiting GAPDH
91% of patients with hematologic malignancies have vitamin C levels that are either low or severly deficient. This study found that vitamin C plus low dose DNA methyltransferase inhibitors have synergistic inhibition of cancer cell proliferation and increased apoptosis. Unfortunately, the authors claimed that oral vitamin C would be sufficient which indicates an incredible lack of understanding of vitamin C pharmacokinetics.