Group items tagged

Other targets of HIF-1α include glucose transporter-1 (GLUT-1), the main transporter involved in glucose uptake [9,10]; lactate dehydrogenase V (LDHV), which is responsible for the conversion of pyruvate into lactate; pyruvate dehydrogenase kinase isozyme 1 (PDK1), which is responsible for the phosphorylation and consequent inactivation of pyruvate dehydrogenase (PDH); and carbonic anhydrase IX (CAIX), a hypoxia-related protein involved in pH regulation [11]. Alpha-methylacyl-CoA racemase (AMACR), pristanoyl-CoA oxidase (ACOX-3) and D-bifunctional protein (DBP), are also important fatty acid oxidation-related proteins in prostate cancer

the essential role played by the cross-talk between stroma and epithelium in carcinogenesis and prostate cancer progression has been increasingly recognised

strong membranous expression of MCT1 was consistently observed in cancer cells, suggesting a role for MCT1 in the transport of lactate into tumour cells from the acidic extracellular matrix, suggesting that lactate might be used as a fuel by oxidative cancer cells.

Our hypothesis is in agreement with those of Fiaschi et al.[17], who describe the metabolic reprogramming of CAFs towards the Warburg phenotype as a result of contact with prostate cancer cells

Using in vitro studies, they showed lactate production and efflux by de novo expressed MCT4 in CAFs and also demonstrated that, upon contact with CAFs, prostate cancer cells were reprogrammed towards aerobic metabolism, with an increase in lactate uptake via the lactate transporter MCT1.

pharmacological inhibition of MCT1-mediated lactate uptake dramatically affected PCa cell survival and tumour outgrowth

In this model, “energy transfer” or “metabolic coupling” between the tumour stroma and epithelial cancer cells fuels tumour growth and metastasis via oxidative mitochondrial metabolism in anabolic cancer cells

the concomitant expression of MCT1 in tumour cells and MCT4 in fibroblasts in the same tissue is clinically significant, and associated with poor prognosis.

Renin catalyses the conversion of AGN to angiotensin I (ATI), which is quickly cleaved by angiotensin converting enzyme (ACE) to form angiotensin II (ATII)

ATII triggers the release of aldosterone from the adrenal glands, which stimulates reabsorption of sodium and water and thereby increases blood volume and blood pressure

ATII also acts on smooth muscle to cause vasoconstriction of the arterioles

ATII promotes the release of antidiuretic hormone from the posterior pituitary gland, which results in water retention and triggers the thirst reflex

ability of non-CSCs to ‘de-differentiate’ into CSCs due to epigenetic or environmental factors, which further increases the complexity of tumour biology and treatment

efficacy of RAS modulators on cancer in both cancer models and cancer patients

A localised (‘paracrine’) RAS mechanism has been identified in many types of cancers, and interruption of the control of the RAS is thought to be the basis for its role in cancer

Components of the RAS are expressed by these CSCs, supporting the hypothesis of the presence of a ‘paracrine RAS’ in regulating these CSCs

Renin is an enzyme normally released by the kidneys in response to falling arterial pressure

a study of GBM demonstrating overexpression of PRR coupled with the observation that inhibition of renin reduces cellular proliferation and promotes apoptosis

PRR has been found to be vital for normal Wnt signalling

A major focus of PRR research is its relationship with Wnt signalling

suggest a crucial role for PRR activation on the proliferation of CSCs, possibly via Wnt/β-catenin signalling, leading to carcinogenesis.

Angiotensin converting enzyme (ACE), also known as CD143, is the endothelial-bound peptidase which physiologically converts ATI to ATII

ACE is crucial in the regulation of blood pressure, angiogenesis and inflammation

results suggest that an overactive ACE promotes cancer growth and progression, and an inhibited or low-activity ACE may have cancer-protective effects

When bound to ATII or ATIII it causes vasoconstriction by stimulating the release of vasopressin, reabsorption of water and sodium by promoting secretion of aldosterone and insulin, fibrosis, cellular growth and migration, pro-inflammation, glucose release from the liver, increased plasma triglyceride concentration, and reduced gluconeogenesis

ATIIR1 is a G-protein-coupled receptor, with downstream signalling involved in vasodilation, hypertrophy and NF-κB activation leading to TNF-α and PAI-1 expression

ATIIR1 has well-documented links with cancer, with one study demonstrating its overexpression in ~20% of breast cancer patients

the effect of RAS dysregulation has been associated with increased VEGF expression and angiogenesis in cancers

In ovarian and cervical cancer, ATIIR1 overexpression has been shown to be an indicator of tumour invasiveness

administration of ATIIR1 blockers (ARBs) have been associated with reduced tumour size, reduction in tumour vascularisation, lower occurrence of metastases, and lower VEGF levels

nother molecule related to cell proliferation that was over-expressed in our data and suggested as a target of downregulated miR-376c is AURKA

the over-expression of miR-183 and miR-21 in Lebanese breast cancer tissues is consistent with downregulation of two important tumor suppressor predicted targets: AKAP12 whose protein regulates cellular adhesion dynamics by controlling cytoskeletal architecture, cell migration, and mitogenic signaling20; and LATS2 whose protein causes cell cycle arrest

dysregulation in cancer particularly in breast cancer highlights their importance in tumor development

mRNA-miRNA integration analysis of early breast cancer revealed a potential role of miRNA in increasing cellular proliferation and progression, and decreasing invasion and migration

most of the miRNA dysregulated in Lebanese breast cancer patients are similar to those dysregulated in American patients, differences in miRNA expression exist and could be attributed either to the patients’ age at diagnosis or to ethnic variation in miRNA epigenetic regulation and sequence variation of pre-miRNA

the number one cancer killer of women worldwide

microRNA (miRNA) are small non-coding 18–25 nucleotide RNA molecules currently being studied as potential diagnostic, prognostic and therapeutic biomarkers for cancer and other diseases

Extensive research on these post-transcriptional modulators has proven that they are deregulated in breast cancerous tissues and even in biological fluids from breast cancer patients

five candidate miRNAs (miR-10b, miR-148b, miR-221, miR-21, and miR-155)

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

On the whole, prospective epidemiological data do not support the hypothesis that the 2-hydroxyestrogen pathway is protective, and the 16α-hydroxyestrogen pathway harmful, in hormone-dependent cancers

Both 2- and 4-hydroxyestrogens are catecholestrogens, and it has been suggested that catecholestrogens increase risk of oestrogen-mediated cancers through direct genotoxic effects, rather than through stimulation of cell proliferation via binding to oestrogen receptors

the evidence is stronger for 4-hydroxyestrogens than for 2-hydroxyestrogens

a significant increase in risk of breast cancer with levels of 2-OHE1 has also been reported previously, although it was limited to hormone receptor-negative tumours

From these observations, it can be concluded that MDA levels play an important role in assessing the outcome of cancer

SOD and CAT are considered primary antioxidant enzymes, since they are involved in direct elimination of reactive oxygen metabolites. [13-16] They also act as anti-carcinogens and inhibitors at initiation and promotion/transformation stage in carcinogenesis

In our study, SOD and CAT levels were found to be low in all cancer patients as compared to controls

Fridovich and Tayarani have demonstrated in their respective studies that the reduction in SOD activity increases the toxic effects of O2 - and this might lead to severe cellular damage.

Mehrotra et al. in their study also observed high levels of MDA and low levels of SOD and CAT in patients of cancer cervix which is in sync with our observations.

strong evidence regarding the definitive role of free radicals in breast malignancy.

Ovarian cancer stem cells play an important role in chemoresistance and cancer recurrence

Furthermore, recent studies indicate that niclosamide exhibits anticancer effects against various human cancer cells by acting on multiple cell signaling pathways and inducing mitochondrial uncoupling [16–21]

has low systemic bioavailability (~10%) when administered orally, which is beneficial for treating local parasitic infections of the intestines while minimizing systemic exposure

The nano-NI demonstrated significantly higher inhibitory effects on sphere formation than the original niclosamide did

the nano-NI formulation decreased the metabolic activity of ovarian cancer cells and caused a metabolic shift from oxidative phosphorylation to glycolysis

This toxicity evaluation showed that oral nano-NI had no toxic effect on either group of mice in terms of weight, plasma albumin levels, and blood cell counts, and revealed no adverse effects on vital organ function in the rodents, which suggests that nano-NI is safe for animals

niclosamide inhibits tumor cell growth by interrupting multiple pathways (Wnt, Notch, STAT3, NF-κB, and mTORc1) and the generation of reactive oxygen species in several cancer cells

The current standard therapy for ovarian cancer includes taxanes and platinum-based chemotherapy after cytoreductive surgery. Among treated patients, nearly 70 to 80% will experience disease recurrence

molecule), cancer cells upregulate glucose receptors and significantly increase glucose uptake in an attempt to ‘catch up

early carcinogenesis often occurs in a hypoxic microenvironment, the transformed cells have to rely on anaerobic GLY for energy production.

Hypoxia-inducible factor (HIF) is activated in hypoxic conditions

evidence suggests that transformation to a glycolytic phenotype offers resistance to apoptosis

non-small cell lung cancer, breast cancer and glioblastoma

Dichloroacetate activated the pyruvate dehydrogenase, which resulted in increased delivery of pyruvate into the mitochondria

DCA increased GO and depolarised the mitochondria, returning the membrane potential towards the levels of the non-cancer cells, without affecting the mitochondria of non-cancerous cells

induction of apoptosis by DCA in non-small cell lung cancer, breast cancer and glioblastoma cell lines

DCA was shown to induce apoptosis in endometrial (Wong et al, 2008) and prostate (Cao et al, 2008) cancer cells

The technique is valuable for predicting the prognosis of patients with recurrent breast cancer and for determining and predicting the outcomes of neoadjuvant chemotherapy

FDG-PET/CT is useful not only for evaluating metastasis but also for predicting the prognosis of recurrent breast cancer and measuring treatment effects

reports remain limited to small-scale clinical trials of about 100 patients.

MaxSUV, which is the most popular FDG-PET/CT value, can vary up to 30 % because of differences among PET/CT devices and among the operators who create the images

the degree of malignancy would increase with an increase in maxSUV when ER or HER-2 signaling is involved.

Factors that determine the rate of cancer progression include T-factor (tumor diameter) and N-factor (presence or absence/number of lymph node metastasis)

The prognostic factors applied in breast cancer can be broadly divided into those that determine staging and those that determine biological tumor characteristics

Prognosis was previously predicted based on T, N, and M staging, which indicates the degree of progression. However, prognosis is now predicted and treatment regimes are presently selected by also considering ER and HER-2 levels, which determine the nature of the tumor

maxSUV presently serves as an indicator of metabolic activity during cancer therapy. For instance, the maxSUV of primary lung and hematological cancer lesions correlates with metastasis and prognosis, whereas maxSUV also seems useful for predicting the prognosis of recurrent breast cancer and in determining and predicting the outcome of neoadjuvant chemotherapy

The maxSUV cut-off calculated from ROC curves for recurrence was 3.0

Factors that determine the nature of tumors also include ER, HER-2, Ki-67 labeling index, and nuclear grade

both ER status and maxSUV as independent prognostic factors

maxSUV has a closer correlation with prognosis

maxSUV, clinical T-factor and ER were significant prognostic factors

Our results showed that maxSUV has the potential to be a novel prognostic factor and that it can be used to determine future therapies

Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration

Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid

ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu

H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents

The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.

Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate

Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration

Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations

For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.

It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.

There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.

H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections

Neutrophils generate H2O2 from superoxide,

i.v. ascorbate is effective in some viral infections

H2O2 is toxic to hepatitis C

Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.

Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose

As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,

Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm

Human Burkitt's lymphoma cells

We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines

Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration

plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption

For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion

All tested normal cells were insensitive to 20 mM ascorbate.

Lymphoma cells were selected because of their sensitivity to ascorbate

As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death

Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure

In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate

Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate

Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.

extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.

H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death

Superoxide dismutase was not protective

Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate

For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased

Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes

There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity

H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media

ascorbate radical is a surrogate marker for H2O2 formation.

whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable

The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.

The occurrence of one predicted complication, oxalate kidney stones, is controversial

In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis

ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.

ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation

data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant

More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis

mice deficient for telomerase or for telomere binding proteins are characterized by accelerated age-related defects

In humans, short telomeres are considered good indicators of an individual’s health status and correlate with both genetic and environmental factors

Although recent findings strongly support the idea that short telomeres drive several age-related diseases 38 we cannot exclude the possibility that in some situations short telomeres may be a consequence of the disease itself.

the current view is that telomerase deficiency may contribute to the early steps of cancer development by fueling chromosomal instability, while subsequent activation of telomerase may be necessary to allow tumor growth and tumor progression towards more malignant states

telomerase activation can be an early event in cancer, it is not necessary for cancer initiation

telomerase can stimulate tumor progression by ensuring maintenance of telomeres above a critically short length, thus preventing induction of cellular senescence or apoptosis

Almost all human cancers present activation of telomerase as a hallmark, most likely as a mechanism to allow unlimited cell proliferation of tumor cells

recent evidence demonstrated that short telomeres alone could lead to genomic instability and cancer

Getting rid of telomerase can also be problematic; the lack of telomerase could lead to increased chromosomal instability, which in turn could be at the basis for cancer initiation when tumor suppressor barriers are bypassed

telomerase activation is a potential therapeutic strategy for the treatment of age-related diseases

telomerase activation in adult or old mice by means of a gene therapy strategy was shown to be sufficient to improve metabolic fitness, neuromuscular capacity, and prevent bone loss, as well as significantly increase both median and maximum longevity, without increased cancer incidence

These studies suggest that telomerase expression could be considered a feasible approach to reverse tissue dysfunction and extend healthy lifespan without increasing cancer incidence

humans almost completely lose telomerase activity from somatic tissues in the adulthood

a change of paradigm seems to be occurring in telomerase biology, with a switch from viewing telomerase as fueling cancer to reversing aging

Telomerase expression in a background of high levels of tumor suppressors or in aged organisms seems to prevent its expected pro-cancer activity and yet it still functions as an anti-aging factor

3β-diol can be a precursor of DHT in prostate cancer cells.

serum 3α-diol G levels reflect the androgen milieu in localized prostate cancer patients receiving ADT

A few studies reported that 3β-diol is a potential ligand of estrogen receptor β (ERβ) and has an antiproliferative effect

our results revealed that 3β-diol is potentially a precursor of DHT in prostate cancer cells

Bauman et al. showed that 3α-diol is inactive at AR, but induces prostate growth

Prostate cancer cells promoted synthesis from the DHT metabolite 3α-diol during the long duration of ADT

verified the synthesis of DHT from 3α- or 3β-diol via different pathways in prostate cancer cells in this study

HSD17B6 expression levels in prostate cancer can be useful for the diagnosis of high-risk prostate cancer

serum 3α-diol G levels reflect the adrenal androgen milieu in localized prostate cancer patients

3α- and 3β-diol has a much more significant role in intratumoral androgen metabolism during ADT

These data suggest that PAA may show a therapeutic advantage to blood cancers vs solid tumors because of the communication between tumor cells and blood plasma

These results strongly suggest that the mechanism of PAA killing of MM cells is indeed iron-dependent

These results suggest that PAA administration in SMM may be able to prevent progression to symtomatic MM

A recent study by Yun and colleagues demonstrated that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, but spares normal cells

RAS family genes show the most frequent mutations in MM. KRAS, NRAS and BRAF are mutated in 22%, 20% and 7% of MM samples

the disease stage rather than the mutation of RAS and/or BRAF is the major predictive factor for PAA sensitivity in MM treatment

Other molecular mechanisms including ATP depletion and ATM-AMPK signaling have been reported to explain PAA-induced cell death

our pilot study also suggested that PAA could overcome drug resistance to bortezomib in MM cells

Our findings complement reported studies and further address the mechanism of action using clinical samples in which we observed that PAA killed tumor cells with high iron content, suggesting that iron might be the initiator of PAA cytotoxicity

combination of PAA with standard therapeutic drugs, such as melphalan, may significantly reduce the dose of melphalan needed

Combined treatment of reduced dose melphalan with PAA achieved a significantly longer progression-free survival than the same dose of melphalan alone.

These data also suggest that the bone marrow suppression induced by high-dose melphalan can be ameliorated by the combination of PAA with lower dose of melphalan because of the lack of toxicity of PAA on normal cells with low iron content.

if creatinine clearance is <30 mL/min, high dose ascorbic acid should be not administrated.

In MM preclinical and clinical studies, ascorbate was used as an adjunct drug and showed controversial results (Harvey et al., 2009, Perrone et al., 2009, Held et al., 2013, Sharma et al., 2012, Nakano et al., 2011, Takahashi, 2010, Sharma et al., 2009, Qazilbash et al., 2008). However, none of these tests used pharmacological doses of ascorbate and intravenous administration

Multiple myeloma (MM) is a plasma cell neoplasm.

Cameron and Pauling reported that high doses of vitamin C increased survival of patients with cancer

pharmacologically dosed ascorbic acid (PAA) 50–100 g (Chen et al., 2008, Padayatty et al., 2004, Hoffer et al., 2008, Padayatty et al., 2006, Welsh et al., 2013), administered intravenously, has potent anti-cancer activity and its role as anti-cancer therapy is being studied at the University of Iowa and in other centers

In the presence of catalytic metal ions like iron, PAA administered intravenously exerts pro-oxidant effects leading to the formation of highly reactive oxygen species (ROS), resulting in cell death

the labile iron pool (LIP) is significantly elevated in MM cells

The survival of CD138+ cells in vitro was significantly decreased following PAA treatment in all 9 MM

In contrast, no significant change of cell viability was observed in CD138− BM cells from the same patients

The same effect of PAA was also observed in the SMM patients

no response to PAA was detected in CD138+ cells from the 2 MGUS patients

the combination of melphalan plus PAA showed greater tumor burden reduction than each drug alone, suggesting a synergistic activity between these two drugs

Both catalase and NAC protect cells from oxidative damage

cells pretreated with NAC and catalase became resistant to PAA even at high doses

adding deferoxamine (DFO), an iron chelator, to OCI-MY5 cells before PAA treatment was also sufficient to prevent PAA-induced cellular death

iron is essential for PAA to achieve its anti-cancer activity

PAA induced early necrosis (Fig. 3Fig. 3A, 60 min) followed by late apoptosis

results further indicated that PAA induced mitochondria-mediated apoptosis

PAA by reacting with LIP and generating ROS induces mitochondria-mediated apoptosis in which AIF1 cleavage is important for cell death.

ROS and H2O2 are well known factors mediating PAA-induced cancer cell death

PAA was sensitive to all 9 MMs and 2 SMMs

Niclosamide treatment inhibited the expression of cyclin D1, Hes1, and PTCH by 33%, 57%, and 79%, respectively

The mechanism via which niclosamide, a protonophoric anthelmintic drug, induces stem-like-cell-specific toxicity in breast cancer is interesting. It is an old drug that has been used to treat tapeworms in animals

Niclosamide was also reported to inhibit Wnt signaling [31]–[33] in colon cancer cells

A screening of autophagy modulators revealed that niclosamide is a novel inhibitor of mTORC1 signaling

A recent work also demonstrated that niclosamide induces the apoptosis of myelogenous leukemic cells via the inactivation of NF-kappaB and reactive oxygen species generation

Niclosamide is known to uncouple mitochondrial oxidative phosphorylation during tapeworm killing

Our recent work demonstrated that niclosamide disrupts multiple metabolic pathways in ovarian-cancer-initiating cells

The present study showed that niclosamide treatment resulted in the downregulation of target genes involved in the self-renewal of cancer stem-like cells and inhibited breast SPS

most conventional radiation and brain cancer chemotherapies can enhance glioma energy metabolism and invasive properties, which would contribute to tumor recurrence and reduced patient survival [34].

We contend that all cancer regardless of tissue or cellular origin is a disease of abnormal energy metabolism

complex disease phenotypes can be managed through self-organizing networks that display system wide dynamics involving oxidative and non-oxidative (substrate level) phosphorylation

As long as brain tumors are provided a physiological environment conducive for their energy needs they will survive; when this environment is restricted or abruptly changed they will either grow slower, growth arrest, or perish [8] and [19]

New information also suggests that ketones are toxic to some human tumor cells and that ketones and ketogenic diets might restrict availability of glutamine to tumor cells [68], [69] and [70].

The success in dealing with environmental stress and disease is therefore dependent on the integrated action of all cells in the organism

Tumor cells survive in hypoxic environments not because they have inherited genes making them more fit or adaptable than normal cells, but because they have damaged mitochondria and have thus acquired the ability to derive energy largely through substrate level phosphorylation

Cancer cells survive and multiply only in physiological environments that provide fuels (mostly glucose and glutamine) subserving their requirement for substrate level phosphorylation

Integrity of the inner mitochondrial membrane is necessary for ketone body metabolism since β-hydroxybutyrate dehydrogenase, which catalyzes the first step in the metabolism of β-OHB to acetoacetate, interacts with cardiolipin and other phospholipids in the inner membrane

the mitochondria of many gliomas and most tumors for that matter are dysfunctional

Cardiolipin is essential for efficient oxidative energy production and mitochondrial function

Any genetic or environmental alteration in the content or composition of cardiolipin will compromise energy production through oxidative phosphorylation

The Crabtree effect involves the inhibition of respiration by high levels of glucose

the Warburg effect involves elevated glycolysis from impaired oxidative phosphorylation

the Crabtree effect can be reversible, the Warburg effect is largely irreversible because its origin is with permanently damaged mitochondria

The continued production of lactic acid in the presence of oxygen is the metabolic hallmark of most cancers and is referred to as aerobic glycolysis or the Warburg effect

We recently described how the retrograde signaling system could induce changes in oncogenes and tumor suppressor genes to facilitate tumor cell survival following mitochondrial damage [48].

In addition to glycolysis, glutamine can also increase ATP production under hypoxic conditions through substrate level phosphorylation in the TCA cycle after its metabolism to α-ketoglutarate

mitochondrial lipid abnormalities, which alter electron transport activities, can account in large part for the Warburg effect

targeting both glucose and glutamine metabolism could be effective for managing most cancers including brain cancer

The bulk of experimental evidence indicates that mitochondria are dysfunctional in tumors and incapable of generating sufficient ATP through oxidative phosphorylation

Cardiolipin defects in tumor cells are also associated with reduced activities of several enzymes of the mitochondrial electron transport chain making it unlikely that tumor cells with cardiolipin abnormalities can generate adequate energy through oxidative phosphorylation

The Crabtree effect involves the inhibition of respiration by high levels of glucose

Warburg effect involves elevated glycolysis from impaired oxidative phosphorylation

TCA cycle substrate level phosphorylation could therefore become another source of ATP production in tumor cells with impairments in oxidative phosphorylation

Caloric restriction, which lowers glucose and elevates ketone bodies [63] and [64], improves mitochondrial respiratory function and glutathione redox state in normal cells

DR naturally inhibits glycolysis and tumor growth by lowering circulating glucose levels, while at the same time, enhancing the health and vitality of normal cells and tissues through ketone body metabolism

DR is anti-angiogenic

DR also reduces angiogenesis in prostate and breast cancer

We suggest that apoptosis resistance arises largely from enhanced substrate level phosphorylation of tumor cells and to the genes associated with elevated glycolysis and glutaminolysis, e.g., c-Myc, Hif-1a, etc, which inhibit apoptosis

Modern medicine has not looked favorably on diet therapies for managing complex diseases especially when well-established procedures for acceptable clinical practice are available, regardless of how ineffective these procedures might be in managing the disease

More than 60 years of clinical research indicates that such approaches are largely ineffective in extending survival or improving quality of life

The process is rooted in the well-established scientific principle that tumor cells are largely dependent on substrate level phosphorylation for their survival and growth

Glucose and glutamine drive substrate level phosphorylation

targeting the glycolytically active tumor cells that produce pro-cachexia molecules, restricted diet therapies can potentially reduce tumor cachexia

It is important to recognize, however, that “more is not better” with respect to the ketogenic diet

Blood glucose ranges between 3.0 and 3.5 mM (55–65 mg/dl) and β-OHB ranges between 4 and 7 mM should be effective for tumor management

PR is an essential modulator of ER-regulated genes but also that it significantly contributes to the prognostic value of ER in ER+/PR+ breast cancers

PR-regulated genes have independent prognostic value, and the presence of PR correlates with favorable clinicopathological outcomes

this study demonstrates that progestin-activated PR redirects ER chromatin binding and functions as a genomic estrogen agonist and as a phenotypic estrogen antagonist in ER+/PR+ breast cancer cells and human tumors

Approximately 80% of ER+ breast cancers are also positive for PR,

In isolation, both hormones activate or inhibit cellular processes in similar directions, although the magnitude of these effects is less for progestin alone than for estrogen alone

PR-mediated antagonism of estrogenic phenotypes is well documented

joint activation of ER and PR antagonized ER-regulated oncogenic processes

In this study, the ratio of the 2-hydroxylation pathway to the 16-hydroxylation pathway was associated with a non-statistically significantly decreased risk of breast cancer

In this study, the ratio of catechols to methylated catechols in the 4-hydroxylation pathway was associated with statistically significantly increased risk of breast cancer.

This result is consistent with the hypothesis that mutagenic quinones derived from 4-hydroxylation pathway catechols contribute to pathogenesis of postmenopausal breast cancer.

Catechols in both the 2- and 4-hydroxylation pathways can be oxidized to form quinones; these reactive electrophiles can then react with DNA to form a variety of adducts

Methylation of the catechols prevents their conversion to reactive quinones

the most common DNA adducts derived from 4-hydroxylation pathway catechols are depurinating and highly mutagenic (7,40), most of those derived from 2-hydroxylation pathway catechols are stable and can be repaired with little error