published ahead of print. The authors conclude that the Testosterone therapy in hypogonadal men with cirrhosis requires further study. They, the authors, state that the risk of Testosterone and hepatocellular carcinoma is overstated. This risk is associated with oral Testosterone replacement and thus in that light is not overstated. The majority of treatment strategies today employ none oral routes of administration which would support their statement.
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.
The activation of each of them leads to an inhibition of adenylyl cyclase via G proteins (Gi/o), which in turn activates many metabolic pathways such as mitogen‐activated protein kinase pathway (MAPK), phosphoinositide 3‐kinase pathway (PI3K), cyclooxygenase‐2 pathway (COX‐2), accumulation of ceramide, modulation of protein kinase B (Akt), and ion channels
phytocannabinoids, endocannabinoids, and synthetic cannabinoids
Action of THC in human organism relies on mimicking endogenous agonists of CB receptors—endocannabinoids
The upregulated expression of CB receptors and the elevated levels of endocannabinoids have been observed in a variety of cancer cells (skin, prostate, and colon cancer, hepatocellular carcinoma, endometrial sarcoma, glioblastoma multiforme, meningioma and pituitary adenoma, Hodgkin lymphoma, chemically induced hepatocarcinoma, mantel cell lymphoma)
concentration of endocannabinoids, expression level of their receptors, and the enzymes involved in their metabolism frequently are associated with an aggressiveness of cancer
CB2 receptor contributes to human epidermal growth factor receptor (HER2) pro‐oncogenic signaling and an overexpression of CB2 increases susceptibility for leukemia development after leukemia viral infection
endocannabinoid‐degrading enzymes are upregulated in cancer cell lines and in human tumors
Many cannabinoids, ranging from phytocannabinoids (THC, CBD), endocannabinoids (2‐arachidonoylglycerol, anandamide), to synthetic cannabinoids (JWH‐133, WIN‐55,212‐2), have shown ability to inhibit proliferation, metastasis, and angiogenesis in a variety of models of cancer
Despite some inconsistent data, the main effect of cannabinoids in a tumor is the inhibition of cancer cells’ proliferation and induction of cancer cell death by apoptosis
CB1 and CB2 receptor agonists stimulate apoptotic cell death in glioma cells by induction of de novo synthesis of ceramide, sphingolipid with proapoptotic activity
process of autophagy is upstream of apoptosis in mechanism of cell death induced by cannabinoids
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.
“Intrinsic processes” include those that result in mutations due to random errors in DNA replication whereas “extrinsic factors” are environmental factors that affect mutagenesis rates (such as UV radiation, ionizing radiation, and carcinogens
intrinsic factors do not play a major causal role.
intrinsic cancer risk should be determined by the cancer incidence for those cancers with the least risk in the entire group controlling for total stem cell divisions
if one or more cancers would feature a much higher cancer incidence, for example, lung cancer among smokers vs. non-smokers, then this most likely reflects additional (and probably extrinsic) risk factors (smoking in this case)
Particularly, for breast and prostate cancers, it has long been observed that large international geographical variations exist in their incidences (5-fold for breast cancer, 25-fold for prostate cancer)14, and immigrants moving from countries with lower cancer incidence to countries with higher cancer rates soon acquire the higher risk of their new country
Colorectal cancer is another high-incidence cancer that is widely considered to be an environmental disease17, with an estimated 75% or more colorectal cancer risk attributable to diet
melanoma, its risk ascribed to sun exposure is around 65–86%
non-melanoma basal and squamous skin cancers, ~90% is attributable to UV
75% of esophageal cancer, or head and neck cancer are caused by tobacco and alcohol
HPV may cause ~90% cases in cervical cancer23, ~90% cases in anal cancer24, and ~70% in oropharyngeal cancer
HBV and HCV may account for ~80% cases of hepatocellular carcinoma
H pylori may be responsible for 65–80% of gastric cancer
While a few cancers have relatively large proportions of intrinsic mutations (>50%), the majority of cancers have large proportions of extrinsic mutations, for example, ~100% for Myeloma, Lung and Thyroid cancers and ~80–90% for Bladder, Colorectal and Uterine cancers, indicating substantial contributions of carcinogen exposures in the development of most cancers
onsistent estimate of contribution of extrinsic factors of >70–90% in most common cancer types. This concordance lends significant credibility to the overall conclusion on the role of extrinsic factors in cancer development