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Vitamin C inhibits GAPDH (a glycolytic enzyme) and depletes the cellular pool of glutathione, resulting in high ROS production and oxidative stress

DoxyR CSCs are between 4- to 10-fold more susceptible to the effects of Vitamin C

Doxycycline and Vitamin C may represent a new synthetic lethal drug combination for eradicating CSCs, by ultimately targeting both mitochondrial and glycolytic metabolism

inhibiting their propagation in the range of 100 to 250 µM

metabolic flexibility in cancer cells allows them to escape therapeutic eradication, leading to chemo- and radio-resistance

used doxycycline to pharmacologically induce metabolic inflexibility in CSCs, by chronically inhibiting mitochondrial biogenesis

This treatment resulted in a purely glycolytic population of surviving cancer cells

DoxyR cells are mainly glycolytic

MCF7 cells survive and develop Doxycycline-resistance, by adopting a purely glycolytic phenotype

Cancer stem cells (CSCs) are thought to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance

the conserved evolutionary similarities between aerobic bacteria and mitochondria, certain classes of antibiotics inhibit mitochondrial protein translation, as an off-target side-effect

Vitamin C was more potent than 2-DG; it inhibited DoxyR CSC propagation by > 90% at 250 µM and 100% at 500 µM

IC-50

DoxyR CSCs are between 4- to 10-fold more sensitive to Vitamin C than control MCF7 CSCs

Berberine, which is a naturally occurring antibiotic that also behaves as an OXPHOS inhibitor

treatment with Berberine effectively inhibited the propagation of the DoxyR CSCs by > 50% at 1 µM and > 80% at 10 µM.

Doxycycline, a clinically approved antibiotic, induces metabolic stress in cancer cells. This allows the remaining cancer cells to be synchronized towards a purely glycolytic phenotype, driving a form of metabolic inflexibility

Doxycycline-driven aerobic glycolysis

new synthetic lethal strategy for eradicating CSCs, by employing i) Doxycycline (to target mitochondria) and ii) Vitamin C (to target glycolysis)

Doxycycline inhibits mitochondrial biogenesis and OXPHOS,

hibits glycolytic metabolism by targeting and inhibiting the enzyme GAPDH

CSCs act as the main promoter of tumor recurrence and patient relapse

a metabolic shift from oxidative to glycolytic metabolism represents an escape mechanism for breast cancer cells chronically-treated with a mitochondrial stressor like Doxycycline, as mitochondrial dys-function leads to a stronger dependence on glucose

Vitamin C has been demonstrated to selectively kill cancer cells in vitro and to inhibit tumor growth in experimental mouse models

many of these actions have been attributed to the ability of Vitamin C to act as a glycolysis inhibitor, by targeting GAPDH and depleting the NAD pool

here we show that DoxyR CSCs are more vulnerable to the inhibitory effects of Vitamin C, at 4- to 10-fold lower concentrations, between 100 to 250 μM

concurrent use of Vitamin C, with standard chemotherapy, reduces tumor recurrence and patient mortality

after oral administration, Vitamin C plasma levels reach concentrations of ~70-220 μM

intravenous administration results in 30- to 70- fold higher plasma concentrations of Vitamin C

pro-oxidant activity results from Vitamin C’s action on metal ions, which generates free radicals and hydrogen peroxide, and is associated with cell toxicity

it has been shown that high-dose Vitamin C is more cytotoxic to cancer cells than to normal cells

This selectivity appears to be due to the higher catalase content observed in normal cells (~10-100 fold greater), as compared to tumor cells. Hence, Vitamin C may be regarded as a safe agent that selectively targets cancer cells

the concurrent use of Doxycycline and Vitamin C, in the context of this infectious disease, appeared to be highly synergistic in patients

Goc et al., 2016, showed that Doxycycline is synergistic in vitro with certain phytochemicals and micronutrients, including Vitamin C, in the in vitro killing of the vegetative spirochete form of Borrelia spp., the causative agent underlying Lyme disease

Doxycycline, an FDA-approved antibiotic, behaves as an inhibitor of mitochondrial protein translation

CSCs successfully escape from the anti-mitochondrial effects of Doxycycline, by assuming a purely glycolytic phenotype. Therefore, DoxyR CSCs are then more susceptible to other metabolic perturbations, because of their metabolic inflexibility

The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors

TLRs are PRRs that recognize microbe-associated molecular patterns

TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain

The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients

Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.

Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption

LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.

In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.

In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.

the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels

dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.

This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.

n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations

it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).

this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A

these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.

This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.

endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis

in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.

T2DM patients have mean values of LPS that are 76% higher than healthy controls

LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic

LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells

Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease

The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile

All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features

LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism

When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome

It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis

On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα

high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs

prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls

Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers

This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation

high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk

LPS has been shown to promote atherosclerosis

markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk

As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.

Gut bacteria in the cecum and large intestine produce SCFAs mainly from nondigestible carbohydrates that pass the small intestine unaffected

plant cell-wall polysaccharides, oligosaccharides, and resistant starches

inulin shifted the relative production of SCFAs from acetate to propionate and butyrate

age of approximately 3–4 years, when it becomes mature

SCFAs affect lipid, glucose, and cholesterol metabolism

colonocytes, the first host cells that take up SCFAs and which depend largely on butyrate for their energy supply

the microbiota educate the immune system and increase the tolerance to microbial immunodeterminants

the microbiota act as a metabolic organ that can break down otherwise indigestible food components, degrade potentially toxic food compounds like oxalate, and synthesize certain vitamins and amino acids

a large part of the SCFAs is used as a source of energy

The general idea is that colonocytes prefer butyrate to acetate and propionate, and oxidize it to ketone bodies and CO2

Exogenous acetate formed by colonic bacterial fermentation enters the blood compartment and is mixed with endogenous acetate released by tissues and organs (103, 104). Up to 70% of the acetate is taken up by the liver (105), where it is not only used as an energy source, but is also used as a substrate for the synthesis of cholesterol and long-chain fatty acids and as a cosubstrate for glutamine and glutamate synthesis

SCFAs regulate the balance between fatty acid synthesis, fatty acid oxidation, and lipolysis in the body.

Fatty acid oxidation is activated by SCFAs, while de novo synthesis and lipolysis are inhibited

obese animals in this study showed a 50% reduction in relative abundance of the Bacteroidetes (i.e., acetate and propionate producers), whereas the Firmicutes (i.e., butyrate producers) were proportionally increased compared with the lean counterparts.

increase in total fecal SCFA concentrations in obese humans.

In humans the distinct relation between the Firmicutes:Bacteroidetes ratio and obesity is less clear.

PAK1 is essential for the growth of more than 70% of all human cancers, including breast, prostate, pancreatic, colon, gastric, lung, cervical and thyroid cancers, as well as hepatoma, glioma, melanoma, multiple myeloma and for neurofibromatosis tumors

Ivermectin suppresses breast cancer by activating cytostatic autophagy, disrupting cellular signaling in the process, probably by reducing PAK1 expression

Cancer stem cells are a key factor in cancer cells developing resistance to chemotherapies and these results indicate that a combination of chemotherapy agents plus ivermectin could potentially target and kill cancer stem cells, a paramount goal in overcoming cancer

Triple-negative breast cancers, which lack estrogen, progesterone and HER2 receptors, account for 10–20% of breast cancers and are associated with poor prognosis

Ivermectin addition led to transcriptional modulation of genes associated with epithelial–mesenchymal transition and maintenance of a cancer stem cell phenotype in triple-negative breast cancers cells, resulting in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo

Ivermectin-induced cytostatic autophagy also leads to suppression of tumor growth in breast cancer xenografts, causing researchers to believe there is scope for using ivermectin to inhibit breast cancer cell proliferation and that the drug is a potential treatment for breast cancer

ivermectin synergizes with the chemotherapy agents cytarabine and daunorubicin to induce cell death in leukemia cells

Ivermectin inhibits proliferation and increases apoptosis of various human cancers

Activation of WNT-TCF signaling is implicated in multiple diseases, including cancers of the lungs and intestine,

A new screening system has found that ivermectin inhibits the expression of WNT-TCF targets

It represses the levels of C-terminal β-catenin phosphoforms and of cyclin D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases

In vivo, ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without side effects

ivermectin has an exemplary safety record, it could swiftly become a useful tool as a WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases, encompassing multiple cancers.117