Anti-tumor research of Amygdalin or Vitamin B17

- Oct 06, 2019-

Amygdalin is mainly found in bitter almonds or extract. In addition to its antioxidant, antibacterial, anti-inflammatory, and immunomodulatory effects, it also has anti-tumor properties. Amygdalin can exert anti-tumor effects in solid tumors such as lung cancer, bladder cancer and renal cell carcinoma by affecting cell cycle, inducing apoptosis, cytotoxicity and regulating immune function.


Amygdalin is one of the main active ingredients of Chinese traditional medicine bitter almond. It has anti-oxidation, anti-bacterial, anti-inflammatory, immune regulation, etc., and has the characteristics of high safety, easy availability and low cost. As early as 1979, the research results on the anti-tumor effect of amygdalin were published.


1. Structural characteristics of amygdalin

In 1803, Schrader first discovered amygdalin. In 1830, Robiquet and others isolated amygdalin from bitter almond. Amygdalin is widely found in the seeds of Rosaceae plants such as apricot, peach and plum, mainly in bitter almond (2%~3%), belonging to aromatic cyanoside. The molecular formula is: C20H27NO11, relative molecular mass. It is 457.43 and contains one unit of benzaldehyde, one unit of hydrogen cyanide and two units of glucose.


2. The basic mechanism of amygdalin against tumor

Amygdalin exerts anti-tumor effects mainly through the following mechanisms.


2.1 Affecting the cell cycle

Tumor cell proliferation was significantly inhibited after intervention of prostate cancer cell lines (LNCaP, DU-145, and PC3) with amygdalin. Flow cytometry revealed that the number of cells in G2/M phase and S phase decreased, while the number of cells in G0/G1 phase increased. At the same time, the expression of cyclin cdk 1, cdk 2 and cdk 4 and cyclin A, cyclin B and cyclin D3 were also decreased by amygdalin. After treatment with human amygdalin (5 mg/mL, 24 h) human colon cancer cells (SNU-C4 cells), cDNA microarray analysis was used to compare gene expression profiles between the untreated and untreated groups, and it was found that amygdalin can be down-regulated. Cell cycle related genes (EXO1, ABCF2, MRE11A, TOP I, FRAP1, etc.) in human colon cancer cells (SNU-C4 cells) affect tumor cell cycle, inhibit cell proliferation, and exert anti-tumor effects.


2.2 Induction of apoptosis

Diffuse almonds were found by 4,6-diamino-2-phenylindole (DAPI) staining (double staining of human cervical cancer HeLa cells treated with amygdalin and annexin V-FITC and propidium iodide PI) Glycosides can promote apoptosis by increasing the activity of Caspase-3 enzyme in HeLa cells. In addition, amygdalin can also induce apoptosis of HeLa cells by down-regulating the expression of anti-apoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic Bax protein. Treatment of prostate cancer cells (DU145 and LNCaP) with amygdalin revealed that amygdalin induces prostate by increasing the expression of pro-apoptotic Bax protein, reducing the expression of anti-apoptotic Bcl-2 protein, and increasing the activity of Caspase-3 enzyme. Apoptosis of cancer cells (DU145 and LNCaP).


2.3 Cytotoxicity

Amygdalin can produce a large amount of hydrocyanic acid under the action of human β-glucosidase, inhibit cytochrome c oxidase (terminal enzyme in mitochondrial respiratory chain), and suspend the synthesis of adenosine triphosphate to induce apoptosis. The rhodanese contained in normal cells converts hydrocyanic acid into non-toxic hydrocyanate, which is absent from tumor cells and thus can be specifically destroyed by hydrocyanic acid. Studies have found that β-glucosidase combined with amygdalin can exert specific anti-tumor effects. The β-glucosidase is bound to the cancer cell surface antigen with the help of an antibody, and then the amygdalin analog is injected to specifically kill the target tumor cell.


A pharmacological and toxicological study found that cyanide was detected in the blood of oral amygdalin (3 times a day, 0.5 g each time), but the experimenter did not show discomfort, and the indicators were normal. The concentration of amygdalin has the effect of selectively killing tumor cells under the action of β-glucosidase in human body, but has no effect on normal cells. The experiment also found that patients taking double doses of amygdalin did not develop cyanide poisoning. Other studies have found that the dose of cyanide poisoning in the human body is 0.5~3.5 g/kg. Systemic toxicity can occur when amygdalin is administered intravenously at 4 g/d for one month. If the daily dose is reduced to 1 g, the toxicity will disappear after stopping the administration.


2.4 Adjusting the body's immune function

Amygdalin is a peptide mimetic of peptide T (PT), an octapeptide for the treatment of psoriasis, and it was verified by Western blot and ELISA that amygdalin can up-regulate TNF-α, IL-10, HSP- 70. Expression of TGF-β and α-v integrin increases the immune function of the body. Amygdalin was intraperitoneally injected into apolipoprotein E-deficient mice, and in vivo Treg amplification/activation analysis revealed increased expression of regulatory T cell-associated cytokines in mice treated with amygdalin. . At the same time, flow cytometry and real-time PCR showed that the percentage of CD4, CD25 and Foxp3 T cells in the amygdalin-treated group was higher than that in the untreated mice, and the expression of FOXP3 (forkhead box P3) was up-regulated. Experiments have shown that amygdalin can regulate the immune function of the body by inhibiting the inflammatory response and increasing the expression of Treg.


3 Research progress of anti-tumor of amygdalin

3.1 Anti-lung cancer

Lung cancer is the malignant tumor with the fastest increase in morbidity and mortality and the greatest threat to the health and life of the population. The highly metastatic cell lines H1299/M and PA/M of non-small cell lung cancer were screened in vitro, and their proliferation, invasion and migration ability were inhibited by amygdalin. Amygdalin can also up-regulate the expression of cadherin E (inhibition of cancer cell metastasis) by down-regulating the expression of both β1 and β4, ILK, FAK, and β-catenin, which promote the metastasis of cancer cells. Phosphorylation levels of AKT and RICTOR, thereby inhibiting the AKT-mTOR signaling pathway.


3.2 Anti-bladder cancer

Bladder cancer ranks first in the incidence of urogenital tumors in China. Amygdalin is administered to UMUC-3 and RT112 bladder cancer cells to examine the adhesion of tumor cells to vascular endothelium or immobilized collagen and tumor cell migration. It has been found that amygdalin can significantly reduce tumor cell adhesion and migration in UMUC-3 and RT112 cells by reducing the expression of integrin alpha and beta isoforms, integrin-linked kinase (ILK) and total activated focal adhesion kinase (FAK). . In vitro study of the role of amygdalin in bladder cancer cell lines (UMUC-3, RT112 and TCCSUP) found that amygdalin reduced the growth and proliferation of three bladder cancer cell lines, mainly by blocking cell cycle progression, Stuck in G0/G1 period. Amygdalin also blocks tumor growth by down-regulating cdk 2 and cyclin A. Amygdalin can also be used as a prodrug for antibody directed enzyme prodrug therapy (ADEPT) for bladder cancer. The β-glucosidase was conjugated to a tumor-associated monoclonal antibody (MAb) (HMFG1), followed by the addition of amygdalin, which was tested for specificity and cytotoxicity in vitro when amygdalin was activated by β-glucosidase. Taking HT1376 bladder cancer cells as an example, amygdalin is cytotoxic to HT1376 bladder cancer cells only at high concentrations, and its binding to HMFG1-β-glucosidase increases cytotoxicity by 36-fold.


3.3 Anti-renal cell carcinoma

The incidence of renal cell carcinoma (referred to as renal cancer, RCC) ranks second in urogenital tumors in China, second only to bladder cancer. Administration of amygdalin (10 mg/mL) to the RCC cell lines Caki-1, KTC-26 and A498 revealed that amygdalin can reduce G2/M phase (Caki-1 and A498) or S phase (KTC-26). Cells, and cells in the G0/G1 phase or S phase, significantly reduce the growth and proliferation of renal cancer cells. In addition, amygdalin can significantly reduce cell cycle activators (especially cdk 1 and cyclin B), E- and N-cadherin. Juengel et al [27] exposed RCC cell lines (Caki-1, KTC-26 and A498) to amygdalin and found that amygdalin reduced the chemotactic and invasive activity of tumor cells. Using FACScan analysis, it was found that amygdalin down-regulated integrin α5 and α6, resulting in a significant decrease in the adhesion of tumor cells to collagen and inhibiting its invasion and metastasis.


3.4 Against other tumors

Various studies have shown that amygdalin can inhibit the proliferation or invasion and metastasis of other malignant tumors such as prostate cancer, breast cancer, cervical cancer, colorectal cancer and leukemia.

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