2021年11月10日水曜日

Cancer treatment aimed at activating AMP-activated protein kinase (AMPK). (Metformin prevents diabetes, cancer, and aging. Berberine contains information on cancer prevention for diabetics.)

Japanese Version.
https://neovisionconsulting.blogspot.com/2021/07/ampampk.html


Reprinted for study.

http://www.1ginzaclinic.com/AMPK.html

[Type 2 diabetes and metabolic syndrome increase the incidence of cancer] When

glucose is absorbed into the body from food and the glucose concentration (blood sugar level) in the blood rises , The action of insulin secreted from the islets of Langerhans in the pancreas lowers the blood sugar level. Insulin is a peptide hormone consisting of 51 amino acids that promotes glucose uptake into muscle cells, fat synthesis in adipocytes, and glycogen synthesis in the liver (see the figure below).



Our body is regulated by the action of insulin so that the blood sugar level does not rise above a certain level, but diabetes is a condition in which the blood sugar level continues to be high due to a decrease in insulin secretion or a weakened function. is.
There are two types of diabetes, type 1 diabetes, which is caused by the destruction of the islets of Langerhans in the pancreas and the inability to secrete insulin, and type 2 diabetes, which is caused by obesity and lack of exercise. It is type 2 diabetes and is characterized by being common among middle-aged and elderly fat people.
Type 2 diabetes is more likely to occur in people with a genetic predisposition (such as those with diabetes who are related), but it does not always occur if there is a genetic predisposition, such as overeating, lack of exercise, obesity, stress, etc. It develops with the addition of the factors of. These dietary habits and lifestyle habits that cause diabetes are consistent with factors that increase the risk of developing or recurring cancer. In other words, the presence of diabetes is expected to increase the incidence of cancer and the recurrence rate after treatment.
Many epidemiological studies have confirmed that diabetes increases the risk of developing cancer. A large-scale survey conducted in Japan (a follow-up survey of the National Cancer Center of about 100,000 people) found that 20 to 30 percent of people with cancer had cancer compared to those who had never been diagnosed with diabetes. It has been shown that the incidence is high. In this study, the incidence of cancer in people with diabetes was 2.24 times higher in liver cancer, 1.92 times higher in kidney cancer, 1.85 times higher in pancreatic cancer, and 1.36 times higher in colorectal cancer in men than in people without diabetes. In the case of women, the results are 2.42 times for ovarian cancer, 1.94 times for liver cancer, and 1.61 times for gastric cancer.
A research group at the National Center for Global Health and Medicine reported this week that it analyzed data for about 257,000 men and women based on papers from around the world since the 1960s. In comparison, the rate of getting some kind of cancer was 11% higher, and the rate of dying from cancer was 16% higher.

It is said that hyperinsulinemia is seen for several years before the onset of type 2 diabetes. Various bioactive substances that affect the function of insulin are secreted from fat cells, and when body fat increases due to obesity, the function of insulin decreases. A protein called adiponectin secreted from adipose tissue has the effect of increasing the action of insulin, but when the visceral fat increases, the amount secreted decreases, and when the blood concentration of adiponectin decreases, insulin resistance (decreased action of insulin) increases. ..
When insulin works weakly, the body tries to compensate by increasing the amount of insulin secreted and increasing the insulin level in the blood to compensate for it. At this stage, diabetes is not diagnosed because the blood sugar level is not very high due to increased insulin secretion, but when sufficient insulin is not secreted from the islets of Langerhans, which secretes insulin, the hyperglycemic state continues and diabetes occurs. You will be diagnosed.
An epidemiological study in the United States reports that people in the pre-diabetes stage (pre-diabetes) are at higher risk of developing cancer than those diagnosed with diabetes. This suggests the importance of the presence of hyperinsulinemia as a cause of increased cancer risk. In other words, it is thought that the diabetic reserve army due to obesity and lack of exercise promotes carcinogenesis by excessively secreting insulin in order to suppress hyperglycemia due to insulin resistance.

Furthermore, it has been pointed out that the cancer progresses quickly and metastasizes easily when diabetes is present. This is because hyperglycemia and hyperinsulinemia promote the growth of cancer cells.
In addition, diabetes causes high blood pressure, arteriosclerotic heart disease, renal disorders and neuropathy, which increases oxidative stress and accelerates aging. It has also been pointed out that insulin has the effect of accelerating aging and shortening lifespan.
Metabolic syndrome is a condition that presents with symptoms such as visceral fat obesity, hyperglycemia, hyperlipidemia, and hypertension. The basis of this condition is the inflammatory condition in adipose tissue and the associated insulin resistance. Gender (a condition in which insulin is less effective) is associated. Metabolic syndrome is known as a risk factor for carcinogenesis, and it is thought that one of the reasons is that it is in a state of hyperinsulinemia due to decreased insulin sensitivity.


[Hyperinsulinemia promotes the growth of cancer cells]

Insulin itself has the effect of promoting the growth of cancer cells. In addition, insulin enhances the activity of insulin-like growth factor-1 (IGF-1), which promotes the growth of cancer cells. Hyperinsulinemia reduces the production of IGF-1 binding proteins that control IGF-1 activity, resulting in increased IGF-1 activity. IGF-1 has the effect of promoting the growth of cancer cells, angiogenesis and metastasis. IGF-1 consists of 70 amino acids and has a structure similar to insulin. The IGF-1 receptor and insulin receptor are similar, and IGF-1 and insulin are known to cross-react. In hyperinsulinemia, insulin binds to the IGF-1 receptor and promotes cell proliferation in the same way as IGF-1.
Furthermore, when blood sugar rises from pre-diabetes to diabetes, cancer cells take up a large amount of glucose as an energy source, which is advantageous for the growth of cancer cells. There is also an opinion that hyperglycemia increases the production of active oxygen, damages vascular endothelial cells and basement membrane, increases vascular permeability, and makes metastasis more likely.
It has been reported that patients with colorectal cancer have higher blood sugar levels and blood insulin levels than healthy people. It has also been pointed out that hyperinsulinemia suppresses the production of sex hormone-binding globulin in the liver, so free estrogen increases in the blood and promotes the growth of breast cancer cells.
For these various reasons, hyperglycemia and hyperinsulinemia increase the risk of cancer cell development, proliferation, and recurrence.

It has been reported that the above-mentioned adiponectin has an anticancer effect. It has been reported that injection of adiponectin into mice transplanted with human gastric cancer cells significantly reduced the cancer. It has also been reported that people with lower adiponectin have a higher incidence of colorectal cancer, prostate cancer, endometrial cancer, breast cancer, and stomach cancer.
It is speculated that this cancer-preventing effect of adiponectin increases insulin sensitivity and lowers blood insulin levels. In other words, it has been pointed out that increasing insulin sensitivity (= reducing insulin resistance) can be expected to be effective in preventing cancer. It has also been shown that adiponectin activates AMP-activated protein kinase (AMPK), which suppresses the growth of cancer cells.


[What is AMP-activated protein kinase (AMPK)]

Insulin resistance is one of the reasons why the risk of cancer increases in diabetes and metabolic syndrome. Insulin becomes less effective and hyperinsulinemia promotes the development and recurrence of cancer.
AMP-activated protein kinase (AMPK) is attracting attention as a factor that improves insulin resistance. AMPK is a type of serine-threonine kinase (serine-threonine kinase) that is highly conserved in eukaryotic cells from humans to yeast, and is a member of the metabolite-sensing protein kinase family. It plays an important role as a sensor of internal energy.
All eukaryotes use a nucleotide called Adenosine Triphosphate (ATP) as energy for cell activity. ATP is said to be the "energy currency of living organisms" and is always used in the reaction process of living organisms that require energy. When ATP is used as energy, ADP (Adenosine Diphosphate) and AMP (Adenosine Monophosphate) increase. In other words, it is decomposed in the order of ATP → ADP + phosphoric acid → AMP + diphosphate, and energy is produced in the process of releasing phosphoric acid.
AMPK is a protein kinase that is activated by this AMP and is activated in response to an increase in AMP in situations where the intracellular ATP supply is depleted, such as low glucose, hypoxia, ischemia, and heat shock. ..
AMPK senses and activates a decrease in intracellular energy (ATP), induces increased catabolism (promotion of ATP production) and suppression of assimilation (suppression of ATP consumption), and has the effect of restoring ATP levels. That is, when AMPK is activated, the synthesis of sugar, fat and protein is suppressed, while the decomposition (catabolism) of sugar, fat and protein is promoted to produce ATP. Therefore, this effect is the same as exercise and is also effective in treating obesity and type 2 diabetes.
AMPK exists as a heterotrimer consisting of three subunits, α, β, and γ, and the complex is activated by the binding of AMP to the γ subunit. Increased AMP / ATP ratios, changes in intracellular pH and reducing status, and increased creatine / phosphocreatine ratios are known to activate AMPK.
In addition, it has been clarified that it is activated by obesity-related cytokines such as leptin and adiponectin and is involved in the control of feeding behavior in the central nervous system, and is considered to play an important role in the metabolic control of the entire individual. I am. Furthermore, in recent years, it has been reported that AMPK has the effect of suppressing the development and growth of cancer and the effect of enhancing the effect of cancer treatment.


[Activation of AMPK suppresses the development and proliferation of cancer cells] In

metabolic syndrome, which is a risk factor for cancer, the activity of AMPK is reduced.
In addition, the activity of AMPK is also suppressed in cancer cells, and it has been reported that activation of AMPK can suppress the growth of cancer cells, and AMPK is regarded as a promising target for cancer prevention and treatment.

Many basic studies such as animal experiments using cultured cancer cells and transplanted tumors have revealed that AMPK activation has the effect of suppressing the growth of cancer cells. AMPK affects the activity of several proteins involved in the regulation of cell proliferation. The following mechanisms have been reported.

1) AMPK activates the tumor suppressor gene p53 and has the effect of suppressing the growth of cancer cells. On the other hand, activation of p53 activates AMPK. In other words, AMPK and the tumor suppressor gene p53 interact to suppress cancer.

2) AMPK inhibits the activities of acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase), which are required for the synthesis of fatty acids and cholesterol. Growth is suppressed when fatty acid synthesis is inhibited by inhibition of ACC. (Note 1)
HMG-CoA reductase is one of the rate-determining enzymes of the mevalonate pathway that synthesizes cholesterol and isoprenoids. Inhibitors of this enzyme are known as statins and are widely used as cholesterol-lowering agents. increase. (Note 2)
AMPK, like statins, inhibits HMG-CoA reductase and inhibits the synthesis of mevalonic acid. Mevalonic acid not only is necessary for cholesterol synthesis, but also makes substances (geranylpyrophophate and farnesylpyrophosphate) necessary for sugar protein synthesis and isoprenylation of GTP-binding protein (G protein). Therefore, if the mevalonate pathway is blocked, the growth of cancer cells will be suppressed. (Note 3)

(Note 1): Insulin activates acetyl-CoA carboxylase (rate-determining enzyme for fatty acid synthesis) and HMG-COA reductase (rate-determining enzyme for cholesterol production in the liver), and fatty acids. And increase cholesterol synthesis. Such effects also promote the growth of cancer cells, but the inhibitory action of ACC and HMG-CoA reductase has the effect of suppressing the growth of cancer cells.
(Note 2): It has been pointed out that statins, which are HMG-CoA reductase inhibitors that inhibit cholesterol synthesis, have a cancer-preventing effect. In addition, it is known that the activity of enzymes involved in the synthesis of fatty acids and cholesterol, such as fatty acid synthase and acetyl-CoA carboxylase, is high in cancer cells. (Breast cancer, prostate cancer, colon cancer, ovarian cancer, etc.) Therefore, inhibiting fatty acid synthesis can suppress the growth of cancer cells.
(Note 3): GTP-binding protein (G protein) is a general term for proteins with endogenous GTP hydrolyzing activity. Among them, the low molecular weight G protein group (Ras, Rho, etc.) has a molecular weight of 20,000 to 30,000. More than 100 types of proteins have been reported so far, and they are involved in intracellular signal transduction as GTP-bound (on) / GDP-bound (off) by translocating to the cell membrane after undergoing isoprenylation. .. When HMG-CoA reductase is inhibited and isoprenoid production is reduced, the activity of low molecular weight G proteins is reduced, resulting in reduced proliferative activity.


3) AMPK inhibits anaerobic glycolysis. In cancer cells, the anaerobic glycolysis system is enhanced, which is known as the Warburg effect. Inhibiting the anaerobic glycolysis of cancer cells is effective in suppressing the growth of cancer cells.

4) AMPK inhibits the mTOR (mammalian target of rapamycin) pathway, suppresses protein synthesis, and inhibits cancer cell proliferation and angiogenesis.
mTOR (mammalian target of rapamycin) is a serine / threonine kinase identified as a target molecule for rapamycin, and is thought to play a central role in the regulation of cell division and survival. Inhibiting the activity of mTOR can inhibit the growth of cancer cells and angiogenesis. mTOR inhibitors are already in clinical use as a treatment for cancer.

Clinically, it has been reported that activation of AMPK reduces the incidence of cancer and enhances the effectiveness of cancer treatment. The anti-cancer effect of AMPK activation has been clarified from the results of research on the diabetes drug Metformin.


[Metformin that increases insulin sensitivity] In
addition to insulin, oral hypoglycemic agents are available as therapeutic agents for diabetes. Oral hypoglycemic agents are a general term for drugs prescribed for the purpose of reducing the risk of diabetic complications by normalizing blood glucose levels in type 2 diabetes, and promote insulin secretion from Langerhans Island in the pancreas. "Insulin secretagogue (sulfonylurea, etc.)", "Glucose absorption inhibitor (alpha glucosidase inhibitor, etc.)" that inhibits glucose absorption from the intestinal tract, "Insulin resistance improving drug (biguanide)" that enhances insulin sensitivity of cells Agents, etc.) ”.
Since insulin promotes the growth of cancer cells and promotes aging, drugs that promote insulin secretion are not preferable from the viewpoint of preventing cancer and aging. In fact, it has been pointed out that drugs that stimulate insulin secretion may increase the incidence of cancer.
On the other hand, many studies have shown that biguanides, which improve insulin resistance and lower blood insulin levels, are effective in preventing aging and cancer.
A biguanide is an organic compound that has a structure in which two guanidine molecules share one nitrogen atom and are linked. Guanidine is produced by the decomposition of guanine (one of the bases that make up nucleic acids) and the metabolism of proteins, and many guanidine derivatives have been found to have physiological activity.
Biguanides are drugs originally developed from guanidine derivatives found in the 1920s in the Middle Eastern legume Galega officinalis, which has a hypoglycemic effect. Biguanides improve glucose metabolism by stimulating the intracellular signaling system via AMP-activated protein kinase (AMPK). That is, it increases the number of insulin receptors in muscle and adipose tissue, increases insulin binding, enhances insulin action, and promotes glucose uptake. In addition, it acts on the liver to suppress gluconeogenesis and suppress glucose absorption in the intestinal tract.
It has been clarified that improving insulin resistance is effective in preventing aging and cancer, and the biguanide drug metformin has also attracted attention as a drug for cancer prevention and anti-aging. I am.

Figure: Hyperglycemia and hyperinsulinemia promote aging and carcinogenesis. Metformin, a diabetes drug, activates AMPK and reduces insulin secretion by increasing insulin sensitivity, which is effective in preventing both carcinogenesis and aging.

[Anti-cancer effect of metformin]

Many studies have shown that metformin, a diabetes treatment drug that improves the action of insulin and suppresses insulin production, suppresses the incidence of cancer.
In a prospective cohort study of 800,000 people conducted in Taiwan, the incidence of colorectal cancer, liver cancer, stomach cancer, and pancreatic cancer in the group with type 2 diabetes and not taking hypoglycemic agents Is about twice as high, and it has been reported that taking metformin lowers it to the level of the non-diabetic group. The paper concludes that 500 mg of metformin daily significantly reduces the incidence of cancer (particularly gastric cancer, colorectal cancer, liver cancer, and pancreatic cancer). (BMC Cancer 2011 Jan 18:11 (1): 20 [Epub ahead of print])
A research group at the University of Texas MD Anderson Cancer Center shows that metformin reduces the risk of pancreatic cancer in diabetics. It is reported from. It has been shown that people with diabetes who took metformin had a 62% reduction in their risk of pancreatic cancer compared to those who did not take metformin. On the other hand, diabetic patients who used insulin or insulin secretagogues had a 4.99-fold and 2.52-fold increased risk of pancreatic cancer, respectively, compared to those who did not. (Gastroenterology 137: 482-488, 2009)
Many studies have shown that metformin is effective in the prevention and treatment of many cancers other than pancreatic cancer, such as lung cancer, colon cancer, and breast cancer.
It has also been reported that metformin has the effect of suppressing the action of a gene protein (HER2: Human epidermal growth factor receptor type 2) that is deeply involved in breast cancer growth, metastasis, and malignancy, and has the effect of inhibiting an enzyme called aromatase that produces estrogen. I am. One epidemiological study reported that taking metformin reduced the incidence of breast cancer by 56%.
Metformin does not increase insulin secretion, but has the effect of improving insulin resistance (increasing the action of insulin and reducing insulin production) and AMP-activated protein kinase (AMPK) that suppresses the growth of cancer cells. It has been pointed out that it may be useful for cancer development prevention, recurrence prevention and cancer treatment even for people who do not have diabetes because it has an activating effect.
Many papers have recently been reported showing the effectiveness of metformin in the treatment of cancer, as shown below.

Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clinical Oncology, 27 (20: 3297-3302, 2009)
Objective: Epidemiological studies suggest that taking the oral hypoglycemic agent metformin is effective in reducing the incidence and mortality of cancer in diabetics. Experiments using cultured cancer cells and animal experiments using transplanted tumors have shown that metformin has the effect of suppressing the growth of cancer cells. However, there are few clinical data supporting the anticancer effect of metformin in human tumors. This study examined the effect of metformin on preoperative chemotherapy for breast cancer patients with diabetes.
Patients and Research Methods: 2529 patients who received preoperative chemotherapy for early breast cancer between 1990 and 2007 at the University of Texas MD Anderson Cancer Center in the United States, of whom metformin was diabetic. 68 patients were taking it, 87 were diabetic who were not taking metformin, and the remaining 2374 were non-diabetic. The resected specimens of the tumor after preoperative chemotherapy were pathologically examined and the rate of complete pathological response was compared.
RESULTS: The complete pathological response of the group who took metformin was 24%, the complete pathological response of the diabetic group who did not take metformin was 8.0%, and the complete pathological response of the non-diabetic group was 16%. there were. The group taking metformin had a higher complete pathological response rate than the group not taking metformin, and the difference was statistically significant.
CONCLUSIONS: In breast cancer patients with diabetes, taking metformin can enhance the effectiveness of preoperative chemotherapy. Further investigation is needed on the anticancer activity of metformin.

(Commentary)
For breast cancer, neoadjuvant chemotherapy and neoadjuvant endocrine therapy are actively used for early-stage breast cancer, which was previously performed immediately in order to further reduce surgical invasion. Is supposed to be done. This makes the tumor as small as possible and allows for a smaller area of ​​conservative therapy. After preoperative chemotherapy, surgical removal of the tumor and pathological examination may show that the cancer has completely disappeared. This is called Pathologic Complete Response (pCR). It is known that if preoperative chemotherapy produces a complete pathological response, recurrence and metastasis are low and the prognosis is good.
The study in this paper is a report from the University of Texas MD Anderson Cancer Center in the United States. Since the number of patients in the metformin group is relatively small at 68, the efficacy of metformin needs to be validated in larger clinical trials, but there is a statistically significant difference that metformin is an anti-breast cancer drug. It can be said that it has the effect of enhancing the effectiveness of cancer drug treatment.
In addition, in this paper, among diabetic patients who did not take metformin, the complete pathological response of the insulin-using group was 0%, whereas the pathological complete response of the insulin-free group was 0%. Was 12%. In other words, it shows that insulin may promote the growth of cancer cells.
In addition to its effect of lowering insulin secretion, it has been reported that metformin enhances the activity of AMP-activated protein kinase, suppresses the growth of cancer cells, and makes it easier to die with anticancer drugs. Diabetes, obesity and lack of exercise are also risk factors for breast cancer, and it has been reported that the recurrence rate is high in the presence of diabetes. Therefore, breast cancer patients with diabetes should take metformin.
In the future, it will be necessary to clarify whether it is useful to administer meoformin to non-diabetic patients.

Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69 (19): 7507-11, 2009
(Summary of the paper) The
reason for cancer recurrence is the presence of cancer stem cells. That is, cancer stem cells that are constantly increasing cancer cells in the cancer tissue and cancer cells that cannot make cancer tissue coexist, and the cancer stem cells are resistant to anticancer drugs. There is an idea that recurrence will occur in order to survive anticancer drug treatment. Therefore, drugs that kill cancer stem cells are desired, but such drugs do not yet exist.
Metformin, which improves insulin resistance and is used to treat diabetes, has the effect of suppressing the development of cancer, and in animal experiments using cultured cancer cells and transplanted tumors, many cancer cells including breast cancer It has been reported that it has an effect of inhibiting the growth of insulin.
In an experiment in which human breast cancer cells were transplanted using nude mice, the effect of suppressing the growth of triple-negative (hormone-independent, Her2-negative) breast cancer cells has been reported. These findings suggest that metformin may be effective in treating cancer, even in non-diabetics.
The paper reports that low doses of metformin have the effect of selectively killing cancer stem cells in breast cancer. Experiments with cultured cancer cells have shown that the combined use of metformin and the usual anticancer drug doxorubicin can kill both non-stem cell cancer cells and cancer stem cells. Furthermore, in animal experiments using transplanted tumors, it was shown that the combined use of the anticancer drug and metformin enhances the effect of shrinking the tumor and preventing recurrence, as compared with the case of the anticancer drug alone. In this animal experiment, treatment with doxorubicin alone resulted in recurrence in 20 days, but combination therapy with doxorubicin and low-dose metformin prevented tumor recurrence for more than 2 months.
The results of these studies suggest that for breast cancer (and perhaps for other cancers), low doses of metformin enhance the effectiveness of conventional antineotherapy.

The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells. Oncol Rep. 25 (1): 135-40. 2011
(Summary)
CD24 is a mucin-like adhesion molecule that promotes metastatic potential of cancer cells and is known as a marker of poor prognosis in breast cancer. It has been reported that many distantly metastasized cancer cells are CD24-positive in treatment-resistant breast cancer. Therefore, suppressing the expression of CD24 in breast cancer cells may be a therapeutic method for suppressing metastasis.
In this study, we showed that the inhibitory effect of metformin on triple-negative breast cancer cells MDA-MB-468 cells was closely associated with the suppression of CD24 protein expression.
Among various breast cancer cells, triple-negative breast cancer cells were found to be particularly sensitive to metformin. In particular, it was confirmed that metformin has a strong inhibitory effect on the growth of breast cancer cells expressing both CD44 and CD24. Metformin suppressed the expression of CD24 protein.
Patients with breast cancer cells with high expression of CD24 were found to have shorter metastasis-free survival.
Taken together, it was suggested that metformin suppresses metastasis and prolongs survival in triple-negative breast cancer with a poor prognosis.

Metformin Treatment Exerts Antiinvasive and Antimetastatic Effects in Human Endometrial Carcinoma Cells. J Clin Endocrinol Metab. 2010 Dec 29. [Epub ahead of print]
[Research Background] Polycystic ovary syndrome is the most common endocrine dysfunction that tends to lead to endometrial proliferation. The purpose of this study was to clarify the effect of metformin, which is used to treat polycystic ovary syndrome, on endometrial cancer cells.
[Purpose and experimental method] The effect of metformin on the infiltration ability and metastatic ability of cultured human endometrial cancer cells was investigated. Since the inflammatory response is closely related to endometrial cancer infiltration and metastasis, the relationship with transcription factors such as NF-kB and matrix metalloproteinase was also investigated.
[Results] When the serum of a patient with polycystic ovary syndrome who took metformin (850 mg twice a day) for 6 months was added to the culture conditions of endometrial cancer cell ECC-1 cells, metformin was not administered. Its infiltration capacity was significantly suppressed as compared with the case where patient serum was added. This action was shown to be mediated by suppression of the signal transduction system of NF-kB, metalloproteinase, Akt and Erk1 / 2, which are activated by inflammation and infiltration and metastasis of cancer cells.
[Conclusion] It was suggested that metformin is useful as an adjunct therapy for endometrial cancer.

Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol . 2010 Dec 17. [Epub ahead of print]
(Summary)
Progesterone is used as a hormone therapy for endometrial cancer, but its response rate is low. The reason is thought to be that the expression rate of progesterone receptors in cancer cells is reduced. Insulin-like growth factor increases the risk of endometrial cancer and suppresses the expression of progesterone receptors in breast cancer cells.
Recent studies have shown that the combination of oral contraceptives and metformin has the effect of improving resistant endometrial atypia with progesterone treatment, but the mechanism is unclear.
In this study, cultured human endometrial cancer cells were used to investigate the effects of metformin on progesterone receptors and insulin-like growth factors, and whether metformin enhances the antitumor effect of progesterone.
As a result, insulin-like growth factors (IGF-I and IGF-II) inhibited the expression of progesterone receptor mRNA and protein, and metformin promoted the expression of progesterone receptor.
In addition, IGF-II promoted the phosphorylation of AKT and p70S6K, and metformin enhanced the phosphorylation of AMP-activated protein kinase and suppressed the phosphorylation of p70S6K. Metformin synergistically enhanced the antitumor effect of progesterone on endometrial cancer cells. The greatest synergistic effect was observed with 1 microM medroxyprogesterone acetate and 10 microm metformin.
From the above results, metformin promotes the expression of progesterone receptor, which is inhibited by IGF-II in endometrial cancer. This effect occurs when metformin activates AMP-activated protein kinase and inhibits the mTOR signaling system activated in cancer cells.

Metformin against TGF-β induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle. 9 (22): 4461-8. 2010.
(Abstract)
Tumor growth factor-beta (TGF-β) causes epithelial-mesenchymal transition, which is active in the pathophysiology of many age-related diseases. It is a major factor. TGF-β-induced epithelial-mesenchymal transition increases the motility of cancer stem cells, causing infiltration and metastasis.
TGF-β-induced epithelial-mesenchymal transition also plays an important role in tissue and organ fibrosis in aging diseases.
Therefore, suppressing TGF-β-induced epithelial-mesenchymal transition suppresses cancer metastasis, and is also effective in the prevention and treatment of organ function deterioration and disorders. Our research group found that metformin, a treatment for type 2 diabetes and metabolic syndrome, markedly suppresses self-renewal and proliferation of breast cancer stem cells that are resistant to trastuzumab (trade name: Herceptin). Is reported. We speculated that TGF-β-induced suppression of epithelial-mesenchymal transition was involved as a mechanism of anticancer action of metformin on cancer stem cells.
TGF-β suppresses the expression of the breast cancer cell MCF-7 epithelial marker E-cadherin, which is inhibited by metformin. Metformin suppresses the enhancement of cancer cell infiltration by TGF-β and the expression of vimentin, a mesenchymal marker.
Based on the above, metformin inhibits TGF-β signaling, suppresses epithelial-mesenchymal transition, and exerts the effect of inhibiting organ fibrosis and cancer progression associated with chronic inflammation. By this mechanism, metformin serves as a therapeutic agent for anti-aging.

(Explanation) Epithelial Mesenchymal Transition (EMT) is a phenomenon in which epithelial cells change their morphology into mesenchymal-like cells. In cancer cells, the acquisition of EMT leads to increased motility, which has been suggested to be associated with infiltration metastasis of cancer cells. (See here for epithelial-mesenchymal transition) In
addition, EMT is also associated with organ fibrosis and functional decline due to chronic inflammation. It is hypothesized that metformin has an inhibitory effect on this EMT, which helps prevent aging and cancer.
In addition to the above, activation of AMP protein kinase by metformin suppresses estrogen production by inhibiting NF-kB activity, P-glycoprotein involved in anticancer drug resistance, and aromatase. Actions have also been reported. Figure: It has been reported that metformin, a therapeutic drug for diabetes, activates AMPK, suppresses the growth, infiltration and metastasis of cancer cells, enhances the effect of anticancer drug treatment, and is also effective in suppressing aging. There is.




From the various studies described above, it seems that taking metformin (about 500 mg daily) is useful in the prevention and treatment of anti-aging and cancer.
Metformin (trade names: Melvin, Metogluco, Medet, Nervis, Metrion, Glycolan, Metformin Hydrochloride Tablets) is inexpensive and highly safe, so taking 500 mg daily without diabetes can prevent cancer and aging. It is useful. (However, because there is interaction and side effects with other drugs, experts and please consult, such as a physician if you want to use)


[Cordyceps Militaris Cordyceps of AMP-activated protein kinase (AMPK) activation action]

that Cordyceps sinensis (Cordyceps sinensis) The term is used in Japan as a general term for mushrooms that parasitize insects. These mushrooms are called the genus Cordyceps, and mushrooms (spores) parasitize insects (mainly larvae of the order Cordyceps and Sheath), and the sclerotium, which is a mass of hyphae, is formed in the body. When the time comes, a rod-shaped fruiting body (aboveground part of the mushroom) is extended from the head and joints of the insect. It is called Cordyceps sinensis because it is an insect in winter and becomes grass (fruiting body) in summer.
On the other hand, "Caterpillar fungus" in China is like a proper noun, and the larvae of the ghost moth are infected with a specific fungus (Cordyceps sinensis). It is a term that refers only to those collected in a specific area (high mountains above 3000 m above sea level such as Qinghai Province and Tibet). This strain does not inhabit Japan.
       
Cordyceps sinensis has long been prized in China as an elixir for immortality and longevity and nutritional tonicity. However, recently, due to its preciousness, it has been drastically reduced due to overfishing and is on the verge of extinction. The yield is less than 10% of 30 years ago, and it has become a target of speculation, and the price has risen more than 1000 times that of 30 years ago, and it is now more than 5 million yen per kg. Cordyceps militaris (Cordyceps militaris) has been attracting attention in China, Japan and South Korea due to the difficulty in obtaining Cordyceps sinensis.
Cordyceps militaris parasitizes various moth pupae or larvae and forms 1 to 10 or more rod-shaped or oblong orange fruiting bodies. It is distributed all over the world such as China, Japan, Canada and Italy.
Since artificial cultivation of Cordyceps militaris is extremely difficult, Chinese researchers have been paying attention to cordyceps militaris as an alternative for about 20 years. The main reason for this is that some cordyceps militaris includes cordycepin, which has an antitumor effect, D-mannitol, which is said to have a vasodilatory effect, β-glucan, which has an immunostimulatory effect, and antioxidants that eliminate active oxygen. This is because it contains abundant physiologically active ingredients such as. In particular, it has been clarified that cordycepin, which has an anti-cancer effect, is contained in cordyceps militaris in a much larger amount than that of Cordyceps militaris.
An artificial cultivation method for cordyceps militaris has been developed, and health foods made from cultivated cordyceps militaris are sold in China, South Korea, and Japan. As a drug, Cordyceps militaris capsule produced by a pharmaceutical company in Changchun in 1997 has been approved by the Chinese government as a new respiratory drug. In recent years, more and more people in China are using Cordyceps militaris as an adjunct to cancer treatment. In China, cordyceps militaris has come to be used as a substitute for the expensive Cordyceps militaris. As for the medicines and health foods made from Cordyceps militaris, which have already been approved and registered in China, it is becoming difficult to obtain Cordyceps militaris due to soaring raw materials, so it seems that the contents are being replaced by cordyceps militaris.
(See here for

Cordyceps militaris and Cordyceps militaris) Many studies on the anticancer effects of Cordyceps sinensis and Cordyceps militaris have been published in studies using cultured cells and animals. There are also reports suggesting its effectiveness in humans. In animal experiments in which cancer cells are transplanted into mice, it has been reported that administration of Cordyceps militaris suppresses the growth of cancer cells and prolongs their lives. Regarding the mechanism of anticancer action of Cordyceps militaris and Cordyceps militaris, immunopotentiating action, antioxidant action, anti-inflammatory action, angiogenesis inhibitory action, and action of directly suppressing the growth of cancer cells have been reported.
Cordycepin is the main component of anticancer activity. It has been reported that cordycepin is more common in cordyceps militaris than in Cordyceps sinensis.
Cordycepin is a substance that KG Gunningham successfully extracted from Cordyceps militaris in 1951, and various physiological activities have been reported. Cordycepin, also called 3'-deoxyadenosine, has a structure in which the hydroxyl group (OH group) is lost from the 3'position of adenosine, which is one of the nucleosides.
Adenosine is one of the nucleosides consisting of adenine and ribose, which is used in the code of genetic information as a base of DNA and RNA, is involved in energy transport as a part of ATP and ADP, and signals as a cyclic AMP. I am involved in communication. Therefore, it is speculated that the efficacy of cordycepin is related to the physiological effects of adenosine and adenosine-1-phosphate (AMP).
Experiments with various cultured cancer cells have reported the inhibitory effect of cordycepin on the growth of cancer cells. As the mechanism of action of the antitumor effect, it has been reported that it has an inhibitory effect on DNA and RNA synthesis, an apoptosis-inducing effect, an inhibition of NF-κB activity of a transcription factor, and an inhibition of cancer cell proliferation signal transduction. It has also been reported to have the effect of suppressing the metastasis of cancer cells. Since cordycepin is an adenosine derivative, it has been reported that it may have an inhibitory effect on cancer cell growth by stimulating adenosine A3 receptors.
It has also been reported that cordycepin activates AMP-activated protein kinase (AMPK), which is activated by adenosine-1-phosphate (AMP). AMPK plays an important role in intracellular signal transduction that suppresses the growth of cancer cells.

Cordycepin has a structure in which the hydroxyl group (OH group) is lost from the 3'position of adenosine. Therefore, if it is incorporated instead of adenosine during DNA or RNA synthesis, it will inhibit DNA or RNA synthesis. Mature messenger RNA (mRNA) has tens to hundreds of bases of adenine (A) added to the 3'end (the one with the hydroxyl group) to form the PolyA tail. It gains stability by having a poly (A) sequence, but cordycepin has been reported to inhibit the poly (A) polymerase that attaches this poly (A) sequence, which may affect cell proliferation and function. I am.
Furthermore, it has been reported that cordycepin-1-phosphate, in which cordycepin is phosphorylated in the body, activates AMPK in place of AMP (Adenosine Mono Phosphate). In other words, cordycepin can activate AMPK because it is similar in structure to adenosine.
Cordyceps militaris contains a few percent of cordycepin, and taking a few grams of cordyceps militaris powder daily is expected to be effective in treating cancer and sarcoma due to the synergistic effect of AMPK activation and other anticancer effects. I can do it.


[Cancer treatment aimed at activating AMPK and inhibiting energy production of cancer cells]
Resveratrol and white flowers contained in red grape skin are components that activate AMPK in the same way as cordycepin contained in Sanagitake. It has been reported that oleanolic acid contained in anti-cancer crude drugs such as serpentine grass and summer dead grass, cryptotancinone contained in tanjin, and berberine contained in Coptis chinensis. Polyphenols, which are abundant in plants, also have an AMP-activating effect.
Oleanolic acid, which is abundant in medicinal herbs, has been reported to be effective against diabetes and ischemic heart disease, and it has been reported that this oleanolic acid activates AMPK. Activation of AMPK works to protect the heart from ischemia. (Int J Physiol Pathophysiol Pharmacol. 2009; 1 (2): 116-126). Oleanolic acid is known to have anti-oxidant, anti-inflammatory, anti-cancer and hepatoprotective effects, but it activates AMPK. Since it also protects the myocardium, it is presumed to be useful for reducing side effects of cancer treatment and enhancing antitumor effects.

Some may argue that adenosine may be effective without taking cordycepin. In fact, it has been reported that adenosine itself has an AMPK activating effect. There is also a report that cordycepin has a stronger AMPK activating effect than adenosine. In addition, Chinese herbs are rich in adenosine and AMP. It also contains components that inhibit adenosine deaminase, which metabolizes adenosine and cordycepin.

Based on the above, several grams of sanagitake per day, 500 mg of metformin per day, herbal medicines rich in oleanolic acid such as white flower snake tongue grass and summer dead grass, and herbal medicines such as Coptis chinensis and Phellodendron aureus containing berberine. When used in combination with a decoction containing, the AMPK of cancer cells can be sufficiently increased and the growth of cancer cells can be suppressed.
Furthermore, when statins and hydroxycitric acid, which inhibit fatty acid synthesis, are used in combination, it is thought that the fatty acid synthesis of cancer cells can be inhibited (the activation of G protein is also inhibited), and cell proliferation can be further suppressed. (When using statins, CoQ10 production in the body decreases, so it is recommended to supplement CoQ10 with supplements.)
In addition to AMPK activation, combined use of sodium dichloroacetate and alpha lipoic acid, which inhibit the anaerobic glycolysis promoted in cancer cells and activate the citric acid cycle and oxidative phosphorylation in mitochondria, is anti-virus. Increases tumor effect.
In addition, the combined use of rapamycin, which directly inhibits mTOR, and crude drug components, which inhibit the PI3K / Akt / mTOR pathway, also enhances the antitumor effect.

Based on the above, metformin + winter worm summer grass + statins (+ CoQ10) + sodium dichloroacetate + alpha lipoic acid + (polyphenols, oleanolic acid, herbal medicines rich in velverin and resveratrol, hydroxycitric acid, etc.) are used for cancer cells. It has a synergistic effect on controlling proliferation and is worth a try.


[Estimated cost for one month]
Metformin 3000 yen Dichloroacetic acid sodium 12000 yen Winter worm summer grass 12000 yen α-lipoic acid & selenium 5000 yen Static drug 6000 yen Chinese herbal medicine about 30,000 yen CoQ10 6300 yen Hydroxycitric acid 6300 yen For questions and inquiries Please email (info@1ginzaclinic.com) or call (03-5550-3552). Home | Introduction of Director | Medical Information | Medical Policy | Book Information | Inquiries |

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