Ovarian cancer is the most lethal gynecologic malignancy and the fifth-most cause of overall cancer death of women in developed countries
An increasingly accepted cancer stem cell hypothesis regards tumors as caricatures of normal organs, possessing a hierarchy of cell types, at various stages of aberrant differentiation, descended from precursor tumor-initiating cells (TIC) cells that are highly resistant to conventional cytotoxics
Significant changes of gene expression in 2,928 genes were identified after niclosamide treatment for different time periods
uncoupling of mitochondrial oxidative phosphorylation is believed to be its anti-helminthic mechanism of action
we hypothesized that niclosamides antagonistic effects on OTICs could, in part, be due to its disruption of metabolism
niclosamide represses metabolic enzymes responsible for bioenergetics, biosynthesis, and redox regulation specifically in OTICs, presumably leading to mitochondrial intrinsic apoptosis pathways, loss of tumor stemness, and growth inhibition
niclosamide treatment resulted in a more than 20% increase in reactive oxygen species (ROS) in cultured OTICs
niclosamide, which has proved to be safe and effective for the past 2 decades against numerous parasites, inhibited OTIC growth both in vitro and in vivo
Our results showed that genes participating in protein complexes of oxidative phosphorylation were downregulated
Niclosamide is believed to inhibit mitochondrial oxidative phosphorylation
Niclosamide was reported to inactivate NF-κB, causing mitochondrial damage and the generation of ROS, leading to apoptosis of leukemic stem cells
niclosamide were identified in a screen for mTOR-signaling inhibitors
mTOR was reported to maintain stemness properties of HSCs by inhibiting mitochondrial biogenesis and ROS levels (39), implying that mTOR inhibitors (such as niclosamide) may interfere with mitochondria and various metabolic pathways in TICs via disruption of antioxidant responses
We observed Wnt hyperactivity in OTICs, in agreement with previous hypotheses of Wnt inhibitor effectiveness as an ovarian cancer therapy
niclosamide has now been independently identified in screens for Wnt inhibitors
downregulation of the Wnt/β-catenin target oncogenes survivin and c-Myc
ovarian carcinogenesis, the cell-to-cell signaling pathway Notch (8), were also suppressed by niclosamide (data not shown). These results agree with another recent niclosamide study in leukemia (49), and it has been widely hypothesized that disruption of Notch signaling may represent a highly effective therapy for ovarian and other solid tumors, via its essentiality to maintaining TIC stemness
Niclosamide, common anti-parasitic medication, inhibits cellular metabolism and increases ROS; both of which provide powerful anti-proliferative, anti-cancer treatment mechanism in TICs. Powerful target therapy for cancer stem cells. Also shown to inhibit Wnt stimulated oncogenes survivin and c-Myc, disrupts Notch signaling, inactivates NF-kappaBeta, and inhibits mTOR-signaling. This has been found in in vitro and in vivo studies.
This broad effect could be a result of niclosamide's pleiotropic activity, similarly affecting signaling pathways that are known to be overly active in human malignant cells (i.e., mTOR, NOTCH, WNT/CTNNB1; refs. 44–46)
It is a salicylanilide that was introduced as a molluscide in 1959
Studies in animals suggested no mutagenic, oncogenic, or embryotoxic activity and no cumulative effects
its rate of absorption from the intestinal tract was estimated at only 33%
the potential mechanism of synergy between temozolomide and niclosamide as a “natural inducer” of NFKBIA
Niclosamide pilot animal study useful in the treatment of Glioblastoma. Found to inhibit NOTCH, mTOR, and WNT and cancer signaling. Also found to reduce the malignant potential through cytostatic, cytotoxic and antimigratory effects of niclosamide on GBM
relative risks imparted by diabetes are greatest (about two fold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2-1.5 fold) for cancers of the colon and rectum, breast, and bladder
Metformin useful in the prevention of cancer, but also on the treatment as an adjunct. Good review through possible mechanisms, mToR, insulin, IGF-1...
TA-1 induces apoptosis through PTEN mediated PI3k/Akt/mTOR pathway inhibition. Sorry, only abstract available here. Significant in that TA-1 works beyond just immune stimulation.
Serine, glycine, glutamine, glutamate, asparagine upregulated in cancer. Most glutamine is converted to glutamate to drive alpha-ketoglutarate production to drive energy production. It also upregulates mTOR signaling.
Calorie restriction and protein restriction inhibit IGF-1, insulin, AkT, PI3K, and mTOR. In addition, those with protein intake >20%, compared to 10%, was associated with a 4 fold increase in cancer death risk and a 75% increase in overall mortality. Protein restriction inhibits tumor growth, associated with a 30-70% reduction in IGF-1, reduced the accumulation of oxidized proteins. The restriction of tryptophan alone reduced inflammation.
metformin augments chemotherapy in the treatment of pancreatic cancer. It promotes the anti-proliferative effects of mTORC and inhibits the proliferative PI3k/mTOR. It also works synergistically with the known anti-tumor anti-malarial drugs chloroquine and with the herb berberine.
Growth hormone plays critical role in breast cancer: promotes angiogenesis, stimulated mTOR, promotes chemoresistance, promotes breast stem activity, promotes metastasis via increase in epithelial to mesenchymal transition...