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Simulated fasting can inhibit triple-negative breast cancer stem cells and enhance the efficacy of targeted drugs
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Sub-Journal of “Cell”: Scientists found that simulated fasting can inhibit triple-negative breast cancer stem cells and enhance the efficacy of targeted drugs
Recently, a new result published in the journal Cell Metabolism explained the detailed mechanism by which FMD restricts tumor progression . It turns out that FMD can inhibit triple negative breast cancer (TNBC) by reducing glucose levels and protein kinase A (PKA) signalingStem cells can activate a variety of drug-targeted pathways in differentiated cancer cells, which means that FMD can effectively enhance the efficacy of related targeted drugs.
The researchers conducted experiments in vitro and in mice. In vitro, low serum and low glucose (STS) were used to simulate FMD. The mice were given a special FMD diet and performed 4 days a week. The calories on the first day were normal diets. 50%, 2-4 days is 10% of normal diet.
The results of the experiment found that STS can reduce the formation of TNBC SUM159 cancer cell spheres; in vivo, FMD can also reduce the frequency of TNBC cell renewal and delay cancer progression. Further analysis found that, FMD increased tumor expression Caspase3, which means that cancer cell apoptosis increased.
This effect can be said to be inseparable from the lowering of blood sugar caused by FMD. When the researchers added 3% glucose to the drinking water of FMD mice, they could partially reverse the tumor suppression effect induced by FMD , which was consistent with the results of in vitro experiments.
Further analysis revealed that the underlying mechanism is the inhibition of the PKA pathway caused by the decrease in glucose.
In other words, FMD reduces TNBC by lowering glucose levels and inhibiting PKAStem cells .
Metastasis is the main cause of death in TNBC patients, so the researchers also observed whether FMD is effective for metastasis.
Experimental results show that both FMD and glycolytic enzyme hexokinase inhibitor 2DG can effectively reduce the metastasis of TNBC in mice, and the anti-metastatic effect of FMD+2DG is even better.
This effect can also be verified to a certain extent in the data set of human patients.
The researchers analyzed a retrospective cohort of patients with advanced TNBC who received platinum-based chemotherapy: they found that patients with hyperglycemia had significantly shorter overall survival (OS) compared with patients with normoglycemia with a baseline blood glucose level of less than 100 mg/dL . With 110mg/dL as the grouping standard, the correlation still exists.
However, in previous studies, although FMD alone can consume cancerStem cells can only delay the growth of tumors , but their improvement in progression-free survival is very limited. Is there still something that can be improved?
Researchers performed RNA sequencing on cancer cells of FMD animals and made some interesting findings. In addition to changes in the level of some pro-apoptotic molecules, FMD also up-regulates the PI3K-AKT pathway and mTOR pathway, and these phenomena only occur in differentiated cells, not cancer stem cells .
This is a wonderful discovery, because PI3K, AKT, mTOR, we all have ready-made medicines!
The researchers tested the effects of the PI3K inhibitor pictilisib, the AKT inhibitor ipatasertib, and the mTOR inhibitor rapamycin in mice, and found that FMD can significantly improve the anti- tumor activity of these inhibitors. Add FMD to get the best results. 85% of mice have PFS for more than 150 days.
In addition, because the up-regulation of these pathways only occurs in differentiated cells, and FMD can inhibit cancer stem cells , the researchers also tried sequential treatments of FMD and FMD+ targeted drugs, and found that FMD can significantly reduce the late emergence of resistance. The possibility of drug properties can better achieve tumor suppression.
However, this is only a pre-clinical study after all, at least the blood sugar reduction effect of FMD on mice and humans is very different. Analysis of clinical studies shows that humans performing FMD for 5 days can reduce blood sugar by about 15%, while in mice it will be reduced by about 40%. Whether cancer patients can bear the “hungry” is also a question that needs to be considered.
Simulated fasting can inhibit triple-negative breast cancer stem cells and enhance the efficacy of targeted drugs.
(source:internet, reference only)