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Life Sci. 2016 Feb 15;147:137-42. doi: 10.1016/j.lfs.2016.01.039. Epub 2016 Jan 29.
Amygdalin delays cell cycle progression and blocks growth of prostate cancer cells in vitro.
Despite impressive survival benefits from new agents to treat metastasized prostate cancer (PCa), progressive drug resistance hinders long-term response and restricts the efficacy of subsequent therapy. Due to reported antitumor activity of amygdalin and growing popularity for complementary and alternative medicine the potential of this natural, widely used substance to exert antineoplastic effects on prostate cancer cells has been assessed.
LNCaP (castration-sensitive), DU-145 and PC3 cells (castration-resistant) were exposed to different concentrations of amygdalin for 24h or 2weeks. Cell growth was measured by the MTT test, clonal formation by the clonogenic assay. Flow cytometry served to investigate apoptosis and cell cycle phases. Cell cycle regulating proteins and the mTOR-akt signaling axis were analyzed by western blotting.
Amygdalin dose-dependently diminished tumor cell growth with maximum effects at 10mg/ml. Apoptosis of PC3 and LNCaP but not of DU-145 cells was reduced, whereas colony formation was suppressed in all cell lines. A decrease in the number of G2/M- and S-phase cells along with an elevated number of G0/G1-phase cells was recorded. The cell cycle proteins cdk 1, cdk 2 and cdk 4 as well as cyclin A, cyclin B and cyclin D3 were modulated by amygdalin after both 24h and 2weeks. Distinct effects on p19 and p27 expression and on Akt, Rictor and Raptor activation became evident only after 2weeks.
Amygdalin exhibits significant antitumor activity in both castration-sensitive and castration-resistant PCa cell lines and merits further evaluation for therapeutic purposes.
Copyright © 2016 Elsevier Inc. All rights reserved.
Int J Mol Med. 2016 Feb;37(2):526-32. doi: 10.3892/ijmm.2015.2439. Epub 2015 Dec 21.
Amygdalin inhibits the growth of renal cell carcinoma cells in vitro.
Although amygdalin is used by many cancer patients as an antitumor agent, there is a lack of information on the efficacy and toxicity of this natural compound. In the present study, the inhibitory effect of amygdalin on the growth of renal cell carcinoma (RCC) cells was examined. Amygdalin (10 mg/ml) was applied to the RCC cell lines, Caki-1, KTC-26 and A498, for 24 h or 2 weeks. Untreated cells served as controls. Tumor cell growth and proliferation were determined using MTT and BrdU tests, and cell cycle phases were evaluated. Expression of the cell cycle activating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1 and D3 as well as of the cell cycle inhibiting proteins p19 and p27 was examined by western blot analysis. Surface expression of the differentiation markers E- and N-cadherin was also investigated. Functional blockade by siRNA was used to determine the impact of several proteins on tumor cell growth. Amygdalin treatment caused a significant reduction in RCC cell growth and proliferation. This effect was correlated with a reduced percentage of G2/M-phase RCC cells and an increased percentage of cells in the G0/1-phase (Caki-1 and A498) or cell cycle arrest in the S-phase (KTC-26). Furthermore, amygdalin induced a marked decrease in cell cycle activating proteins, in particular cdk1 and cyclin B. Functional blocking of cdk1 and cyclin B resulted in significantly diminished tumor cell growth in all three RCC cell lines. Aside from its inhibitory effects on growth, amygdalin also modulated the differentiation markers, E- and N-cadherin. Hence, exposing RCC cells to amygdalin inhibited cell cycle progression and tumor cell growth by impairing cdk1 and cyclin B expression. Moreover, we noted that amygdalin affected differentiation markers. Thus, we suggest that amygdalin exerted RCC antitumor effects in vitro.
PMID: 26709398 DOI: 10.3892/ijmm.2015.2439
[Indexed for MEDLINE]
PLoS One. 2014 Aug 19;9(8):e105590. doi: 10.1371/journal.pone.0105590. eCollection 2014.
Amygdalin blocks bladder cancer cell growth in vitro by diminishing cyclin A and cdk2.
Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25-10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin’s practical value as an anti-tumor drug.
Emerg Med Australas. 2015 Oct;27(5):491-2. doi: 10.1111/1742-6723.12462. Epub 2015 Aug 20.
Apricot kernels: a rare case of cyanide toxicity.
PMID: 26289124 DOI: 10.1111/1742-6723.
Can J Physiol Pharmacol. 1983 Nov;61(11):1426-30.
High-dose ascorbic acid decreases detoxification of cyanide derived from amygdalin (laetrile): studies in guinea pigs.
Cysteine, a sulphur-containing amino acid, is required to metabolize ascorbic acid (as ascorbate sulphate) and detoxify cyanide (to thiocyanate). In guinea pigs, conjoint use of laetrile (a cyanogenic glycoside) and ascorbic acid (in large doses) decreases the detoxification of cyanide derived from laetrile through diminishing the availability of cysteine, but not impairing hepatic rhodanese activity, which is involved in the detoxification of cyanide to thiocyanate. These results agree with the symptoms of a sublethal dose of KCN toxicity manifested by the animals. The studies, therefore, indicate that individuals taking megadoses of ascorbic acid concurrently with laetrile may be subject to self-poisoning.
Ann Pharmacother. 2005 Sep;39(9):1566-9. Epub 2005 Jul 12.
Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C.
To describe a case of severe accidental cyanide poisoning following a single ingestion of amygdalin with therapeutic intent.
A 68-year-old patient with cancer presented to the emergency department shortly after her first dose (3 g) of amygdalin with a reduced Glasgow Coma Score, seizures, and severe lactic acidosis requiring intubation and ventilation. The patient also ingested 4800 mg of vitamin C per day. She responded rapidly to hydroxocobalamin treatment. The adverse drug reaction was rated probable on the Naranjo probability scale.
Amygdalin and laetrile (a synthetic form of amygdalin) are commonly used as complementary or alternative medicine (CAM) for the treatment of cancer. Vitamin C is known to increase the in vitro conversion of amygdalin to cyanide and reduce body stores of cysteine, which is used to detoxify cyanide. Amygdalin has been used for decades by patients with cancer who are seeking alternative therapies, and severe reactions have not been reported with this dose. An interaction with vitamin C is a plausible explanation for this life-threatening response.
This case highlights the fact that CAMs can produce life-threatening toxicity. This case also adds a further note of caution, namely, the potential for serious interactions between CAMs, particularly where there is no tradition of concomitant use.
PMID: 16014371 DOI: 10.1345/aph.1E634
[Indexed for MEDLINE]
Cochrane Database Syst Rev. 2015 Apr 28;(4):CD005476. doi: 10.1002/14651858.CD005476.pub4.
Laetrile treatment for cancer.
Laetrile is the name for a semi-synthetic compound which is chemically related to amygdalin, a cyanogenic glycoside from the kernels of apricots and various other species of the genus Prunus. Laetrile and amygdalin are promoted under various names for the treatment of cancer although there is no evidence for its efficacy. Due to possible cyanide poisoning, laetrile can be dangerous.
To assess the alleged anti-cancer effect and possible adverse effects of laetrile and amygdalin.
We searched the following databases: CENTRAL (2014, Issue 9); MEDLINE (1951-2014); EMBASE (1980-2014); AMED; Scirus; CINAHL (all from 1982-2015); CAMbase (from 1998-2015); the MetaRegister; the National Research Register; and our own files. We examined reference lists of included studies and review articles and we contacted experts in the field for knowledge of additional studies. We did not impose any restrictions of timer or language.
Randomized controlled trials (RCTs) and quasi-RCTs.
DATA COLLECTION AND ANALYSIS:
We searched eight databases and two registers for studies testing laetrile or amygdalin for the treatment of cancer. Two review authors screened and assessed articles for inclusion criteria.
We located over 200 references, 63 were evaluated in the original review, 6 in the 2011 and none in this update. However, we did not identify any studies that met our inclusion criteria.
The claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data. There is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion. The risk-benefit balance of laetrile or amygdalin as a treatment for cancer is therefore unambiguously negative.
- Laetrile treatment for cancer. [Cochrane Database Syst Rev. 2011]
PMID: 25918920 DOI: 10.1002/14651858.CD005476.pub4
[Indexed for MEDLINE]
Neth J Med. 2013 Nov;71(9):496-8.
Cyanide intoxication by apricot kernel ingestion as complimentary cancer therapy.
[Indexed for MEDLINE] Free
Wien Med Wochenschr. 2015 May;165(9-10):185-8. doi: 10.1007/s10354-014-0340-7. Epub 2015 Jan 22.
Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child.
The use of complementary and alternative medicine (CAM) is widespread in children with cancer and is poorly regulated.
PATIENTS AND METHODS:
We describe a case of severe cyanide poisoning arising from CAM use. A severely agitated, encephalopathic, unresponsive 4-year-old boy (initial Glasgow Coma Scale of 3) with a history of metastatic ependymoma was brought to our emergency department by ambulance services. Initial blood gas analysis demonstrated severe metabolic/lactic acidosis. On detailed questioning of the parents, the use of CAM including intravenous and oral “vitamin B 17″ (amygdalin) and oral apricot kernel was reported. After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen. Serum cyanide level was markedly elevated.
Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides.
PMID: 25605411 DOI: 10.1007/s10354-014-0340-7
- Format: Abstract
N Engl J Med. 1982 Jan 28;306(4):201-6.
A clinical trial of amygdalin (Laetrile) in the treatment of human cancer.
One hundred seventy-eight patients with cancer were treated with amygdalin (Laetrile) plus a “metabolic therapy” program consisting of diet, enzymes, and vitamins. The great majority of these patients were in good general condition before treatment. None was totally disabled or in preterminal condition. One third had not received any previous chemotherapy. The pharmaceutical preparations of amygdalin, the dosage, and the schedule were representative of past and present Laetrile practice. No substantive benefit was observed in terms of cure, improvement or stabilization of cancer, improvement of symptoms related to cancer, or extension of life span. The hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range. Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment.
PMID: 7033783 DOI: 10.1056/NEJM198201283060403
[Indexed for MEDLINE]
Does use of alternative medicine in addition to conventional therapies predict prolonged survival from cancer? Even if the alternative therapies themselves were useless, one might predict users would live longer, because they tend to have more hope, a greater will to live; nearly three times as likely to believe their cancer was curable even if it wasn’t. But death rates were actually higher in alternative medicine users. Follow them up years later, and 79 percent of the alternative medicine users had died compared to 65 percent of nonusers. Now if the alternative medicine users started out sicker, that could certainly explain that, and they did tend to be, though the difference didn’t reach statistical significance. Bottom line: the association between the use of alternative medicine and shortened survival is not necessarily cause and effect, but it’s possible some of the alternative modalities may have indeed been harmful.
Thanks to the internet, there has been a resurgence of older complementary and alternative cancer treatments, such as laetrile, which is a compound derived from amygdalin, a natural cyanide-containing substance concentrated in apricot kernels, the seeds inside the pits. It was branded as a “vitamin” to skirt regulations—vitamin B-17—but it’s not a vitamin, and the lack of laetrile’s effectiveness against cancer and the risk of side effects from cyanide poisoning led to it being banned decades ago. However, no surprise, you can still buy it on the internet, along with the apricot kernels themselves. Why not just give them a try, though? Because of cyanide intoxication.
Here’s a typical case report. Woman ate some apricot seeds she got at a health food store. So, they’ve got to be healthy, right? Twenty minutes later, she was having trouble breathing, before she slipped into a coma. They made some calculations, and it appears an eight-ounce bag of apricot kernels is enough to kill six people if consumed in one sitting. “Therefore, the continuing sale of apricot kernels as health food is troubling.”
And you never know what you’re getting. Here, this person was consuming a quarter of a teaspoon of ground apricot kernels daily, and had just switched brands the day before she ended up in the ICU. Thankfully, she survived; others are not so lucky, like this 17-year-old who was dead within a day, as severe cyanide poisoning can result in coma, convulsions and cardiovascular collapse. That’s why calling it a vitamin is so insidious. A 32-year-old woman arrives at the emergency room in a coma. Was she on anything? No, she just took some vitamin supplements. Thankfully, a relative showed up with them. Oh, B-17. They gave her a cyanide antidote and she survived. But had that relative not showed up, or been delayed in traffic or something, the case could have proved fatal.
So, “[c]ancer patients should be informed about the high risk of developing serious adverse effects due to cyanide poisoning after laetrile or amygdalin,” the natural compound in apricot seeds. Especially at risk may be those taking megadoses of vitamin C, or those not getting enough vitamin B12. See, the body has two major ways to detoxify cyanide. It can attach it to B12 to form the supplement form cyanocobalamin, which can be harmlessly peed out. Or, it can use the amino acid cysteine, which is also used to metabolize vitamin C, and so if you take too much vitamin C, levels can drop, and you can end up more vulnerable to cyanide toxicity.
But hey, conventional cancer treatments such as chemo can be toxic, too. It’s all about benefits versus risks. Yeah, amygdalin can block the growth of certain cancer cells in a petri dish, though doesn’t appear to have any anti-cancer effects against laboratory animal tumors. But you don’t know what happens in people…until you put it to the test and do a clinical trial of amygdalin in the treatment of human cancer, which we’ll cover next.
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- Thomson D. Complementary, alternative, proven, unproven. Intern Med J. 2006;36(10):623-4.
- Beadle GF, Yates PM, Najman JM, et al. Beliefs and practices of patients with advanced cancer: implications for communication. Br J Cancer. 2004;91(2):254-7.
- Smith PJ, Clavarino AM, Long JE, Anstey CM, Steadman KJ. Complementary and alternative medicine use by patients receiving curative-intent chemotherapy. Asia Pac J Clin Oncol. 2016;12(3):265-74.
- Milazzo S, Horneber M. Laetrile treatment for cancer. Cochrane Database Syst Rev. 2015;(4):CD005476.
- Ginter E, Simko V. False claims about so called vitamin B 17. Bratisl Lek Listy. 2013;114(4):241.
- Lerner IJ. Laetrile: a lesson in cancer quackery. CA Cancer J Clin. 1981;31(2):91-5.
- O’brien B, Quigg C, Leong T. Severe cyanide toxicity from ‘vitamin supplements’. Eur J Emerg Med. 2005;12(5):257-8.
- Seghers L, Walenbergh-van veen M, Salome J, Hamberg P. Cyanide intoxication by apricot kernel ingestion as complimentary cancer therapy. Neth J Med. 2013;71(9):496-8.
- Sadoff L, Fuchs K, Hollander J. Rapid death associated with laetrile ingestion. JAMA. 1978;239(15):1532.
- Sauer H, Wollny C, Oster I, et al. Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child. Wien Med Wochenschr. 2015;165(9-10):185-8.
- Moertel CG, Fleming TR, Rubin J, et al. A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N Engl J Med. 1982;306(4):201-6.
- Makarević J, Tsaur I, Juengel E, et al. Amygdalin delays cell cycle progression and blocks growth of prostate cancer cells in vitro. Life Sci. 2016;147:137-42.
- Chan TY. A probable case of amygdalin-induced peripheral neuropathy in a vegetarian with vitamin B12 deficiency. Ther Drug Monit. 2006;28(1):140-1.
- Suchard JR, Wallace KL, Gerkin RD. Acute cyanide toxicity caused by apricot kernel ingestion. Ann Emerg Med. 1998;32(6):742-4.
- Vlad IA, Armstrong J, Bertilone C, Matisons M. Apricot kernels: a rare case of cyanide toxicity. Emerg Med Australas. 2015;27(5):491-2.
- Basu TK. Possible toxicological aspects of megadoses of ascorbic acid. Chem Biol Interact. 1977;16(2):247-50.
- Bromley J, Hughes BG, Leong DC, Buckley NA. Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C. Ann Pharmacother. 2005;39(9):1566-9.