cancer stem cells may also contribute to tumor formation, metastasis, and treatment resistance
Studies have shown that some agents (such as metformin) can selectively target cancer stem cells and that dietary polyphenols, curcumin, peperine, and sulforaphane, which are derived from broccoli/broccoli sprouts, are able to target breast cancer stem cells via inhibition of the Wnt signaling, which affects mammosphere size and colony formation
niclosamide inhibits tumor growth and reduces tumor weight
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
Previous studies from our laboratory have demonstrated that pharmacological ascorbate is cytotoxic to pancreatic cancer cells while normal cells are resistant
Ascorbate-induced cytotoxicity is mediated by the formation of H2O2 during the oxidation of ascorbate
the combination of IR + ascorbate increased the concentration of intracellular H2O2
Under steady-state conditions, intracellular GSH is maintained at millimolar concentrations, which keeps cells in a reduced environment and serves as the principal intracellular redox buffer when cells are subjected to an oxidative stressor including H2O2 (26). Glutathione peroxidase (GPx) activity catalyzes the reduction of H2O2 to water with the conversion of GSH to glutathione disulfide (GSSG). Under steady-state conditions, GSSG is recycled back to GSH by glutathione disulfide reductase using reducing equivalents from NADPH. However, under conditions of increased H2O2 flux, this recycling mechanism may become overwhelmed leading to a depletion of intracellular GSH (27, 28).
ascorbate radiosensitization can create an overwhelming oxidative stress to pancreatic cancer cells resulting in oxidation/depletion of the GSH intracellular redox buffer, resulting in cell death.
Treatment with the combination of ascorbate + IR significantly delayed tumor growth compared to controls or ascorbate alone
Ascorbate + IR also significantly increased overall survival compared to controls, IR alone or ascorbate alone
54% of mice treated with the combination of IR + ascorbate had no measurable tumors
Glutathione is a measurable marker indicative of the oxidation state of the thiol redox buffer in cells. In severe systemic oxidative stress, the GSSG/2GSH couple may become oxidized, i.e. the concentration of GSH decreases and GSSG may increase because the capacity to recycle GSSG to GSH becomes rate-limiting
This suggests that the very high levels of pharmacological ascorbate in these experiments may have a pro-oxidant toward red blood cells as seen by a decrease in the capacity of the intracellular redox buffer
These data support the hypothesis that ascorbate radiosensitization does not cause an increase in oxidative damage from lipid-derived aldehydes to other organs.
Our current study demonstrates the potential for pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
pharmacological ascorbate enhances IR-induced cell killing and DNA fragmentation leading to induction of apoptosis in HL60 leukemia cells
pharmacological ascorbate significantly decreases clonogenic survival and inhibits the growth of all pancreatic cancer cell lines as a single agent, as well as sensitizes cancer cells to IR
Hurst et al. demonstrated that pharmacological ascorbate combined with IR leads to increased numbers of double-strand DNA breaks and cell cycle arrest when compared to either treatment alone
pharmacological ascorbate could serve as a “pro-drug” for the delivery of H2O2 to tumors
the double-strand breaks induced by H2O2 were more slowly repaired
The combination of ascorbate and IR provide two distinct mechanisms of action: ascorbate-induced toxicity due to extracellular production of H2O2 that then diffuses into cells and causes damage to DNA, protein, and lipids; and radiation-induced toxicity as a result of ROS-induced damage to DNA. In addition, redox metal metals like Fe2+ may play an important role in ascorbate-induced cytotoxicity. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of H2O2; labile iron can also react with H2O2. Recently our group has demonstrated that pharmacological ascorbate and IR increase the labile iron in tumor homogenates from this murine model of pancreatic cancer
we demonstrated that ascorbate or IR alone decreased tumor growth, but the combination treatment further inhibited tumor growth, indicating that pharmacological ascorbate is an effective radiosensitizer in vivo
data suggest that pharmacological ascorbate may protect the gut locally by decreasing IR-induced damage to the crypt cells, and systemically, by ameliorating increases in TNF-α
related to
intracellular hydrogen peroxide generation
only be obtained by
intravenous administration of AA
Preferentially kills neoplastic cells
Is virtually non-toxic at any dosage
Does not suppress the immune system, unlike most chemotherapy
agents
Increases animal and human resistance to infectious agents by
enhancing lymphocyte blastogenesis, enhancing cellular immunity,
strengthening the extracellular matrix, and enhancing bactericidal
activity of neutrophils and modulation of complement protein
Strengthens the structural integrity of the extracellular matrix
which is responsible for stromal resistance to malignant invasiveness
1969, researchers at the NCI reported AA was highly toxic to Ehrlich
ascites cells in vitro
In 1977, Bram et al reported preferential AA
toxicity for several malignant melanoma cell lines, including four
human-derived lines
Noto et al reported that AA plus vitamin K3
had growth inhibiting action against three human tumor cell lines at
non-toxic levels
Metabolites of AA have also shown antitumor activity in
vitro
The AA begins to reduce cell proliferation in the tumor cell
line at the lowest concentration, 1.76 mg/dl, and is completely cytotoxic to
the cells at 7.04 mg/dl
the normal cells grew at an enhanced rate at the low dosages (1.76
and 3.52 mg/dl)
preferential toxicity of AA for tumor
cells. >95% toxicity to human endometrial adenocarcinoma and pancreatic
tumor cells (ATCC AN3-CA and MIA PaCa-2) occurred at 20 and 30 mg/dl,
respectively.
No toxicity or inhibition was demonstrated in the normal,
human skin fibroblasts (ATCC CCD 25SK) even at the highest concentration of
50 mg/dl.
the use of very high-dose intravenous AA for the treatment of
cancer was proposed as early as 1971
Cameron and Pauling have published
extensive suggestive evidence for prolonged life in terminal cancer patients
orally supplemented (with and without initial intravenous AA therapy) with
10 g/day of AA
AA, plasma levels during infusion were not monitored,
the long-term, oral dosage used in those experiments (10 g/day),
while substantial and capable of producing immunostimulatory and
extracellular matrix modulation effects, was not high enough to achieve
plasma concentrations that are generally cytotoxic to tumor cells in
culture
This low cytotoxic level of AA is exceedingly rare
5 — 40 mg/dl of AA is required in vitro to kill 100% of tumor
cells within 3 days. The 100% kill levels of 30 mg/dl for the endometrial
carcinoma cells and 40 mg/dl for the pancreatic carcinoma cells in Figure 2
are typical
normal range (95% range) of 0.39-1.13 mg/dl
1 h after beginning his first 8-h infusion of 115 g AA (Merit
Pharmaceuticals, Los Angeles, CA), the plasma AA was 3.7 mg/dl and at 5 h
was 19 mg/dl. During his fourth 8-h infusion, 8 days later, the 1 h plasma
level was 158 mg/dl and 5 h was 185 mg/dl
plasma levels of over 100 mg/dl have been maintained in 3
patients for more than 5 h using continuous intravenous infusion
In rare instances of patients with widely disseminated
and rapidly proliferating tumors, intravenous AA administration (10 — 45
g/day) precipitated widespread tumor hemorrhage and necrosis, resulting in
death
Although the outcomes were disastrous in these cases, they are
similar to the description of tumor-necrosis-factor-induced hemorrhage and
necrosis in mice (52) and seem to demonstrate the ability of AA to kill
tumor cells in vivo.
toxic effects of AA on one normal cell line were observed at 58.36 mg/dl and
the lack of side effects in patients maintaining >100 mg/dl plasma levels
Although it is very rare, tumor necrosis, hemorrhage, and subsequent
death should be the highest priority concern for the safety of intravenous
AA for cancer patients.
Klenner,
who reported no ill effects of dosages as high as 150 g intravenously over a
24-h period
Cathcart (55) who
describes no ill effects with doses of up to 200 g/d in patients with
various pathological conditions
following circumstances: renal
insufficiency, chronic hemodialysis patients, unusual forms of iron
overload, and oxalate stone formers
Screening for red cell glucose-6-phosphate
dehydrogenase deficiency, which can give rise to hemolysis of red blood
cells under oxidative stress (57), should also be performed
any cancer therapy should be started at a low dosage to ensure
that tumor hemorrhage does not occur.
patient is orally supplementing between infusions
a scorbutic rebound effect can be
avoided with oral supplementation. Because of the possibility of a rebound
effect, measurement of plasma levels during the periods between infusions
should be performed to ensure that no such effect takes place
Every effort
should be made to monitor plasma AA levels when a patient discontinues
intravenous AA therapy.
Studies have shown that the production of nagalase has a mutual relationship with Gc-MAF level and immunosuppression
It has been demonstrated that serum levels of nagalase are good prognosticators of some types of cancer
The nagalase level in serum correlates with tumor burden and it has been shown that Gc-MAF therapy progresses, nagalase activity decreases
It has been shown that Gc-MAF can inhibit the angiogenesis induced by pro-inflammatory prostaglandin E1
The effect of Gc-MAF on chemotaxis or activation of tumoricidal macrophages is likely the main mechanism against angiogenesis.
Administration of Gc-MAF stimulates immune-cell progenitors for extensive mitogenesis, activates macrophages and produces antibodies. “This indicates that Gc-MAF is a powerful adjuvant for immunization.”
Cancer cell lines do not develop into tumor genes in mouse models after Gc-MAF-primed immunization (29-31) and the effect of Gc-MAF has been approved for macrophage stimulation for angiogenesis, proliferation, migration and metastatic inhibition on tumors induced by MCF-7 human breast cancer cell line
The protocol included: "a high dose of second-generation Gc-MAF (0.5 ml) administered twice a week intramuscularly for a total of 21 injections.”
Yamamoto et al. showed that the administration of Gc-MAF to 16 patients with prostate cancer led to improvements in all patients without recurrence
Inui et al. reported that a 74-year-old man diagnosed with prostate cancer with multiple bone metastases was in complete remission nine months after initiation of GcMAF therapy simultaneously with hyper T/NK cell, high-dose vitamin C and alpha lipoic acid therapy
It has also been approved for non-neoplastic diseases such as autism (41), multiple sclerosis (42, 43), chronic fatigue syndrome (CFS) (40), juvenile osteoporosis (44) and systemic lupus erythematous (45).
Gc-MAF has been verified for use in colon, thyroid (38), lung (39), liver, thymus (36), pancreatic (40), bladder and ovarian cancer and tongue squamous carcinoma
Prostate, breast, colon, liver, stomach, lung (including mesothelioma), kidney, bladder, uterus, ovarian, head/neck and brain cancers, fibrosarcomas and melanomas are the types of cancer tested thus far
weekly administration of 100 ng Gc-MAF to cancer at different stages and types showed curative effects at different follow-up times
this treatment has been suggested for non-anemic patients
Studies have shown that weekly administration of 100 ng Gc-MAF to cancer patients had curative effects on a variety of cancers
Because the half-life of the activated macrophages is approximately one week, it must be administered weekly
In vivo weekly intramuscular administration of Gc-MAF (100 ng) for 16-22 weeks was used to treat patients with breast cancer
individuals harboring different VDR genotypes had different responses to Gc-MAF and that some genotypes were more responsive than others
Administration of Gc-MAF for cancer patients exclusively activates macrophages as an important cell in adaptive immunity
Gc-MAF supports humoral immunity by producing, developing and releasing large quantities of antibodies against cancer. Clinical evidence from a human model of breast cancer patients supports this hypothesis
There is also evidence that confirms the tumoricidal role of Gc-MAF via Fc-receptor mediation
It is likely that the best therapeutic responses will be observed when the nutritional and inflammatory aspects are taken together with stimulation of the immune system
it should be noted that no harmful side effects of Gc-MAF treatment have been reported, even when it was successfully administered to autistic children
The natural activation mechanism of macrophages by Gc-MAF is so natural and it should not have any side effects on humans or animal models even in cell culture
Besides the Gc-MAF efficacy on macrophage activity, it can be a potential anti-angiogenic agent (28) and an inhibitor of the migration of cancerous cells in the absence of macrophages (47).
Activating or modifying natural killer cells, dendritic cells, DC, CTL, INF and IL-2 have all been recommended for cancer immunotherapy
It has been reported that nagalase cannot deglycosylate Gc-MAF as it has specificity for Gc globulin alone
inflammation-derived macrophage activation with the participation of B and T lymphocytes is the main mechanism
macrophages highly-activated by the addition of Gc-MAF can show tumoricidal activity
Previous clinical investigations have confirmed the efficacy of Gc-MAF. In addition to activating existing macrophages, Gc-MAF is a potent mitogenic factor that can stimulate the myeloid progenitor cells to increase systemic macrophage cell counts by 40-fold in four days
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.
This hypothesis has now been confirmed by experimental evidence showing that doxycycline reduces tumor burden in a mouse model of breast cancer-derived osteolytic bone metastasis
IL-2 is a central T cell-derived cytokine, which induces NK cell and T cell proliferation, differentiation and activation, and also stim-ulates the production of secondary immunostimulatory cytokines
combination of histamine and IL-2 thus triggers efficient NK cell-mediated killing of several types of leukemic cells, including freshly recovered human AML blasts
histamine improves the effects of IL-2 on T cell activation
principal action of histamine is to protect cytotoxic lymphocytes from myeloid-cell-induced inactivation, thus improving the efficiency of the T and NK cell stimulation achieved by IL-2
random-ized Phase II study of patients with renal cell carcinoma further support the suggestion that the combination of HDC and IL-2 improves lymphocyte functions
HDC improves the effectiveness of IL-2-induced T and NK cell activation in cancer patients, as predicted in preclinical models
histamine dihydrochloride enhances immune effects of NK cells in IL02 therapy; specifically in this analysis in AML, the histamin prevented inactivation of the IL-2 activated NK cells.
The switch may also involve down-regulation of endogenous inhibitors of angiogenesis such as endostatin, angiostatin or thrombospondin (reviewed in [5]) and has thus been regarded as the result of tipping the net balance between positive and negative regulators
There is a complex interrelationship between tumor hypoxia and tumor angiogenesis
Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth
HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)
When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways
c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.
mTOR can also promote stabilization and HIF transcriptional activity
hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment
Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration
Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments
The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group
Resveratrol inhibits capillary endothelial cell growth and new blood vessel growth in animals
[155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha
resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha
prevents cytokine-induced vascular leakage and tumor metastasis
The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors
Hyperthermia differs fundamentally from fever in that it elevates the core body temperature without changing the physiological set point
hyperthermia is induced by increasing the heat load and/or inactivating heat dissipation
mor cells [2]. Although significant cell killing could be achieved by heating cells or tissues to temperatures > 42°C for 1 or more hours, the application, measurement and consistency of this temperature range within the setting of cancer clinical trials
mild temperature hyperthermia (ie, within the fever-range, 39–41°C)
they are key regulators of cellular protein activity, turnover and trafficking
Hsps ensure appropriate post-translational protein folding, and are able to refold denatured proteins, or mark irreversibly damaged proteins for destruction
the ability of fever-range hyperthermia to induce reactive immunity against tumor antigens through DCs and NK-cells is likely mediated by Hsps
thermotolerance
Hsps support the malignant phenotype of cancer cells by not only affecting the cells’ survival, but also participating in angiogenesis, invasion, metastasis and immortalization mechanisms
Hsps released from stressed or dying cells activate dendritic cells (DCs), transforming them into mature APCs
In theory, fever-range hyperthermia may take advantage of tumor cell Hsps by inducing their release from tumor cells and augmenting DC priming against tumor antigens
In several models of hyperthermia, heat-treated tumors exhibited improved DC priming and generation of systemic immunity to tumor cell
hyperthermia alone can enhance antigen display by tumor cells, thus rendering them even more susceptible to programmed immune clearance
Fever-range hyperthermia may also induce Hsps
Hsps may exert an adjuvant effect by bolstering MHC class II and co-stimulatory molecule expression by DCs
thermal ablation of liver tumors in particular has demonstrated an ability to potentiate immune responses [57, 58] and elicit robust T-cell infiltrates at ablation sites
specific Hsp, Hsp70, directly inhibits apoptosis pathways in cancer cells, as demonstrated in human pancreatic, prostate and gastric cancer cells
Cross-priming is the ability of extracellular Hsps complexed to tumor peptides to be internalized and presented in the context of MHC class I molecules on APCs, thus allowing potent priming of CTLs against tumor antigens
It has been reported that Hsps are generated from necrotic tumor cell lysates, but not from tumor cells undergoing apoptosis
tumor cells exposed to hyperthermia in the heat shock range (42°C for 4h) prior to lysing, DC activation and cross-priming were significantly enhanced with the application of heat
Due to the ability of Hsps to activate DCs directly by chaperoning tumor antigens upon their release [28], it is possible that both local and regional immune stimulation can be achieved with hyperthermia.
support the use of hyperthermia as an inducer of Hsps to serve as ‘danger signals’, activating antitumor immune responses
whole-body hyperthermia not only augments immune responses, but also stimulates the migration of skin-derived DCs to draining lymph nodes
Hyperthermia increased NK cell activation, proliferation, and infiltration, which equals increased cytotoxicity.
exposure to fever-range hyperthermia resulted in improved endogenous NK-cell cytotoxicity to several cancer types
improved activation and function of DCs and NK cells following hyperthermia
Hyperthermia increases the expression ICAM-1 a key adhesion molecule,
The combined effects of hyperthermia on lymphoid tissue endothelium and lymphocytes can promote immune surveillance and increase the probability of naive lymphocytes leaving the circulation and encountering their cognate antigen displayed by DCs in lymphoid organs.
In independent clinical studies, whole-body hyperthermia resulted in a transient decrease in circulating lymphocytes in patients with advanced cancer [12, 94, 99, 100], a finding which mirrored observations in animal models in which lymphocyte entry into lymph noeds was increased following hyperthermia treatment [93]. Enhanced recruitment of lymphocytes to lymphoid tissues may be exploited in the treatment of malignancies.
The initial tumor antigen presentation and initiation of clonal expansion of CTLs transpires in the lymph nodes and cannot take place outside this specialized compartment
the ability of DCs present in the lymph nodes to stimulate an anti-tumor immune response is critical
hyperthermia has been shown to improve immune surveillance by T-cell
MicroRNAs (miRNAs), a major family of small RNAs, are ∼23 nt-long single strands of RNA that bind to mRNA transcripts to inhibit their translation
A recent study by Zhang et al. reported that plant-derived miRNAs can be found in human serum.
The group demonstrates that the plant miRNA miR168 may be taken up through dietary intake to inhibit the expression of its target low-density lipoprotein receptor 1 in the liver21, providing the first evidence that miRNA in food may influence gene expression in mammalian organs.
A more recent finding by the same group shows that a plant miRNA from honeysuckle is able to inhibit Influenza A replication22, indicating that plant miRNAs may be useful for treating human diseases.
We found that plant miR159 could be detected in human sera and its levels were inversely correlated with BC incidence and progression.
We further identified TCF7 as a mammalian target for miR159 and showed the anti-proliferative function of miR159 in BC cells using in vitro and in vivo models, demonstrating for the first time that a plant miRNA is able to influence BC cell growth.
certain dietary miRNAs from plants and other species may serve as highly affordable and powerful means of treatment with minimal inconvenience to patients.
miR159 which (using a synthetic mimic) targets TCF7 to inhibit the proliferation of cells whose growth is dependent on TCF7 such as the BC cells MDA-MB-231
our study using a BC model clearly indicates the anti-tumor effect of orally administered synthetic miR159 in its naturally existing form with the plant-specific 2'-O-methylation, suggesting the feasibility of using synthetic forms of plant miRNAs as dietary supplements in the treatment of human cancers, including those outside of the GI track