IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production
IR is known to induce EMT in vitro
p53 is activated in response to IR-induced DNA damage
IR paradoxically also promotes tumour recurrence and metastasis
DNA double-strand breaks (DSBs)
cancer cells undergoing EMT acquire invasive and metastatic properties
changes in the tumour microenvironment (TME)
IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism
EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
IR is known to induce stemness and metabolic alterations in cancer cells
transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
Loss of E-cadherin is considered a hallmark of EMT
IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
ROS are known to play an important role in IR-induced EMT
High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT
Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion
IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
NF-κB signalling that promotes cell migration
ROS promote EMT to allow cancer cells to avoid hostile environments
HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
IR induces vascular damage that causes hypoxia
ROS is implicated in IR-induced HIF-1 activation
IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
TGF-β signalling has been shown to play a crucial role in IR-induced EMT
AP-1 transcription factor is involved in IR-induced TGF-β1 expression
Wnt/β-catenin signalling is also implicated in IR-induced EMT
Notch signalling is known to be involved in IR-induced EMT
IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail
PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
ROS and RNS are also implicated in IR-induced EGFR activation
IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT
IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,
signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451
Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes
EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
some CSC subpopulations arise independently of EMT
IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
IR has been shown to induce reprogramming of differentiated cancer cells into CSCs
In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
metabolic reprogramming
HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
metabolic reprogramming
tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis
occurring within the same tumour
CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen
mitochondrial function is crucial for maintaining CSC functionality
cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
HIF-1 then enhances glycolysis
CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
STAT3 has been implicated in EMT-induced metabolic changes as well
TGF-β and Wnt play important roles in the metabolic alteration of cancer cells
Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness
EMT, invasion, metastasis, and stemness
pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis
LDH catalyses the bidirectional conversion of lactate to pyruvate
High levels of LDHA are positively correlated with the expression of EMT and CSC markers
IR has been shown to induce metabolic changes in cancer cells
IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
Lactate can activate latent TGF-
lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
intrinsic immunogenicity or induce tolerance
cancer immunoediting’
three phases: 1) elimination, 2) equilibrium, and 3) escape.
The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis
IR-induced Snail increases MMP-2 expression to promote EMT
Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness
IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
Metabolic alterations
oncogenic metabolism
elicit various changes in the TME
Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
Five branched chain and aromatic amino acids (isoleucine, leucine, valine, tyrosine, and phenylalanine) showed significant associations with future diabetes
there is increasing evidence that longer term high-protein intake may have detrimental effects on insulin resistance [68, 117–123], diabetes risk [69], and the risk of developing cardiovascular disease
high-protein and the high GI diets significantly increased markers of low-grade inflammation
significant and clinically relevant worsening of insulin sensitivity with an isoenergetic plant-based high-protein diet
healthy humans that are exposed to amino acid infusions rapidly develop insulin resistance
longer term high-protein intake has been shown to result in whole-body insulin resistance [68, 118], associated with upregulation of factors involved in the mammalian target of rapamycin (mTOR)/S6K1 signalling pathway [68], increased stimulation of glucagon and insulin within the endocrine pancreas, high glycogen turnover [118] and stimulation of gluconeogenesis [68, 118].
it was recently shown in a large prospective cohort with 10 years followup that consuming 5% of energy from both animal and total protein at the expense of carbohydrates or fat increases diabetes risk by as much as 30% [69]. This reinforces the theory that high-protein diets can have adverse effects on glucose metabolism.
Another recent study showed that low-carbohydrate high-protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are also associated with increased risk of cardiovascular disease [70], thereby indicating a potential link between high-protein Western diets, T2DM, and cardiovascular risk.
Serum concentrations of BCAAs are decreased, while the concentrations of the aromatic amino acids (AAAs) phenylalanine and tyrosine are increased, in patients with advanced liver diseases, resulting in a low ratio of BCAAs to AAAs, a ratio called the Fischer ratio
BCAAs were reported to stimulate the production of hepatocyte growth factor
a simplified Fischer ratio, the BCAA to tyrosine ratio (BTR), has been reported useful for predicting serum albumin concentration one year later
BCAA supplementation was shown to delay the progression of CCl4-induced chronic liver injury in a rat model by reducing hepatic apoptosis
BCAAs promoted hepatocyte regeneration in a rat model of hepatectomy
BCAA supplementation for advanced cirrhotic patients improves nutritional status and quality of life
BCAAs activate mTOR and subsequently increase the production of eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase, which upregulate the synthesis of albumin
BCAAs were shown to improve homeostasis model assessment scores for insulin resistance (HOMA-IR) and beta cell function (HOMA-%B) in patients with chronic liver disease, indicating that BCAAs can ameliorate insulin resistance
Several clinical trials have suggested that BCAA supplementation improves the prognosis of cirrhotic patients
A low Fischer ratio has been associated with hepatic encephalopathy
Treatment with BCAAs may therefore have a beneficial effect on patients with hepatic encephalopathy mainly by compensating decreased ratio of BCAAs to AAAs, but not by reducing serum ammonia levels
Two randomized studies also showed that BCAAs did not clearly prevent HE in patients with advanced cirrhosis, although BCAAs prevented the progression of hepatic failure
a systematic review with meta-analyses on the effect of oral BCAAs for the treatment of HE was published[66]. The review has revealed that supplementation of oral BCAAs in cirrhotic patients inhibits the manifestation of HE, especially in patients with overt HE rather than those with minimal HE, but showed no effect on the survival of those patients[66]. Thus, oral administration of BCAAs is the treatment of choice in cirrhotic patients with HE
Cisplatin and 5-FU or CAP (cisplatin, doxorubicin, and cyclophosphamide) regimens can be used for combination chemotherapy
patients with advanced salivary gland malignancy treated with the CAP regimen achieved partial response (PR) or stable disease (SD) rates of 67% (8 out of 12 patients)
Agents commonly given as monotherapy for treating ACC are cisplatin, mitoxantrone, epirubicin, vinorelbine, paclitaxel, and gemcitabine. However, few of these agents have shown efficacy
single agent mitoxantrone or vinorelbine were recommended as reasonable choices
ACC is subdivided into 3 histological groups based on solid components of the tumor including cribriform, tubular, and solid
Cribriform and tubular ACCs usually exhibit a more indolent course, whereas the solid subtype is associated with worse prognosis
ACC consists of two different cell types: inner luminal epithelial cells and outer myoepithelial cells
epithelial cells express c-kit, cox-2 and Bcl-2
myoepithelial cells express EGFR and MYB
a balanced translocation of the v-myb avian myeloblastosis viral oncogene homolog-nuclear factor I/B (MYB-NFIB) is considered to be a signature molecular event of ACC oncogenesis
As a transcription factor, MYB is known to modulate multiple genetic downstream targets involved in oncogenesis, such as cox-2, c-kit, Bcl-2 and BclX
Various signaling cascades are essential for cancer cells to survive and grow. The PI3K/Akt/mTOR pathway is one of them
This pathway regulates cell survival and growth and is upregulated in many cancers
Mutations in genes associated with DNA repair are frequently found in familial cancer syndromes, such as hereditary breast-ovarian cancer syndrome (HBOC), hereditary non-polyposis colorectal cancer (HNPCC, also called Lynch syndrome) and Li-Fraumeni syndrome [30, 31]. These mutations were also reported in non-hereditary cancers
70% of ACC samples (58 of 84) were found to have genetic alterations in the MYB/MYC pathway, indicating that changes in this pathway are crucial in ACC pathogenesis
The second most frequently mutated pathway was involved in chromatin remodeling (epigenetic modification), a pathway that includes multiple histone related proteins, and was altered in 44% of samples
C-kit
VEGF, iNOS and NF-κB were noted to be highly expressed in ACC cells as compared to normal salivary gland cells
members of the SOX family, such as SOX 4 and SOX10, are overexpressed in ACC
FABP7 (Fatty acid binding protein 7) and AQP1 (Aquaporin 1) tend to be overexpressed in ACC cell lines
considerable variability in HER2 overexpression ranging from 0–58% in patients with ACC
the study with cetuximab and concurrent chemoradiation or chemotherapy showed the highest ORR (total 43%, 9.5% CR and 33% PR), but this regimen was only given to the EGFR positive patients
Cancer immunotherapy can be classified into 3 major groups. Active immunization using anti-tumor vaccines to induce and recruit T cells, passive immunization based on monoclonal antibodies, and adoptive cell transfer to expand tumor-reactive autologous T cells ex vivo and then reintroduce these cells into the same individual
LAK cells showed cytotoxicity against ACC cells
cytokine-induced cell apoptosis and the cytotoxic effect of the LAK cells contributed to tumor regression
molecular finding of the MYB-NFIB fusion gene has the greatest potential to target what appears to be a fundamental event in disease pathogenesis
Accumulating evidence suggests that niclosamide targets multiple signaling pathways such as nuclear factor-kappaB (NF-kB), Wnt/β-catenin, and Notch, most of which are closely involved with cancer stem cell proliferation
The transcription factor NF-κB has been demonstrated to promote cancer growth, angiogenesis, escape from apoptosis, and tumorigenesis
NF-κB is sequestered in the cytosol of resting cells through binding the inhibitory subunit IκBα
Niclosamide blocked TNFα-induced IκBα phosphorylation, translocation of p65, and the expression of NF-κB-regulated genes
Niclosamide also inhibited the DNA binding of NF-κB to the promoter of its target genes
niclosamide has two independent effects: NF-kB activation and ROS elevation
The Wnt signaling pathway plays fundamental roles in directing tissue patterning in embryonic development, in maintaining tissue homeostasis in differentiated tissue, and in tumorigenesis
niclosamide is a potent inhibitor of the Wnt/β-catenin pathway
The Notch signaling pathway plays important roles in a variety of cellular processes such as proliferation, differentiation, apoptosis, cell fate decisions, and maintenance of stem cells
niclosamide potently suppresses the luciferase activity of a CBF-1-dependent reporter gene in both a dose-dependent and a time-dependent manners in K562 leukemia cells
niclosamide treatment abrogated the epidermal growth factor (EGF)-stimulated dimerization and nuclear translocation and transcriptional activity of Stat3, and induced cell growth inhibition and apoptosis in several types of cancer cells (e.g. Du145, Hela, A549) that exhibit relatively higher levels of Stat3 constitutive activation
niclosamide can rapidly increase autophagosome formation
niclosamide induced autophagy and inhibited mammalian target of rapamycin complex 1 (mTORC1)
Niclosamide has low toxicity in mammals (oral median lethal dose in rats >5000 mg/kg
Niclosamide is active against cancer cells such as AML and colorectal cancer cells, not only as a monotherapy but also as part of combination therapy, in which it has been found to be synergistic with frontline chemotherapeutic agents (e.g., oxaliplatin, cytarabine, etoposide, and daunorubicin)
Because niclosamide targets multiple signaling pathways (e.g., NF-κB, Wnt/β-catenin, and Notch), most of which are closely involved with cancer stem cells, it holds promise in eradicating cancer stem cells
Review article: common anti-parasitic medication, niclosamide, provides anti-proliferative effect in cancer stem cells (CSC), via inhibition of NF-kappaBeta, Wnt/B-catenin, Notch, ROS, mTORC1, and STAT2 pathways.
however, 100 mg/kg of niclosamide could suppress the growth of the relatively slow-growing tumor (CRC039) to the same level
niclosamide was confirmed to inhibit the growth of human CRCs in NOD/SCID mice
niclosamide can inhibit Wnt pathway activation in CRC
The mechanism of action of the niclosamide in our studies is thought to be through internalization of Fzd1 and downregulation of Wnt pathway intermediaries
Recently, Jin et al. (26) reported that niclosamide inhibited the NF-κB pathway and increased reactive oxygen species levels to induce apoptosis in AML cells. In contrast, we did not observe any inhibitory effect of niclosamide on NF-κB signaling in our CRC model
oral administration of niclosamide does result in sufficient distribution of the drug into tumor tissue, to prove a prolonged inhibitory effect on Wnt/ß-catenin signaling, resulting in tumor growth inhibition
we required higher doses (100 ~ 200 mg/kg body weight) of niclosamide in order to demonstrate significant inhibition of tumor growth in NOD/SCID mice
niclosamide concentrations in tumor tissue showed good correlation with those in plasma, suggesting the efficient distribution of niclosamide from blood to tumor tissue
we observed downregulation of Dvl2 and ß-catenin cytosolic expression in niclosamide-treated tumor cells in vivo
One potential concern for the use of niclosamide as an anticancer therapy is the poor absorption of this drug
The Wnt signaling pathway, fundamental to embryonic tissue patterning, is also activated in stem-like cells
The canonical Wnt pathway is activated in approximately 80% of sporadic CRC primarily due to mutations in the APC gene
recent observations reveal that Wnt ligands or inhibitors may affect the growth and survival of colon cancer cells in spite of the presence of APC or CTNNB1 mutations
Niclosamide found to inhibit Wnt/B-catenin signaling pathway, and thus promotion of apoptosis, in colorectal cancer cells in Vivo study. It was also found to augment chemotherapeutic.
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
To date nearly half of known human tumors show a dysregulation of the WNT signaling pathway
It should be also noted that the WNT pathway is not exclusively employed during development or overactivated in cancer. In adults many healthy tissues rely on it for renewal and homeostasis maintenance, most notably the intestine, haematopoietic system, hair, bones and skin. Therefore one might expect adverse reactions in all these organ systems, which has indeed been observed for many WNT-targeting compounds upon attempts to push them into the clinics
The intestine seems to be the most vulnerable in this regard
Ivermectin inhibits proliferation of human colon cancer and lung cancer cells both in vitro and in vivo
The anti-proliferative action, affecting both the bulk tumor cells and CSCs, was linked in this study to inhibition of WNT signaling
the anti-WNT IC50 of ivermectin is 5–10 times (~1–2 µM vs. 10 µM) lower than that of its toxic effect against chloride channels
oral bioavailability of the drug, as for other antiparasitic drugs discussed in this section, is very low
Toxicity studies in vivo have also demonstrated a wide therapeutic index for ivermectin
Its anti-proliferative activity has been demonstrated in a wide array of cancer cell lines representative of WNT-dependent cancers: non-small lung carcinoma [96], multiple myeloma [97], hepatoma [98], adrenocortical carcinoma [99], ovarian cancer [100] and glioblastoma
Niclosamide inhibits the canonical WNT pathway
In addition to inhibiting the canonical WNT pathway, niclosamide may mediate its anticancer activities through several other signaling pathways such as NOTCH [107], MTOR [108], NF-κB [97] and STAT3 [96]
review article highlights older medications that have anti-Wnt pathway effects in cancer. Roughly, 50% of cancer involve upregulated Wnt pathway activity. Other drugs of note: metformin