NAC and Prostate

NAC and Prostate

 

1.
Mol Cancer Ther. 2014 Mar 31. [Epub ahead of print]

Natural compound Alternol induces oxidative stress-dependent apoptotic cell death preferentially in prostate cancer cells.

Abstract

Prostate cancers at the late stage of castration resistance are not responding well to most of current therapies available in clinic, reflecting a desperate need of novel treatment for this life-threatening disease. In this study, we evaluated the anti-cancer effect of a recently isolated natural compound Alternol in multiple prostate cancer cell lines with the properties of advanced prostate cancers in comparison to prostate-derived non-malignant cells. As assessed by trypan blue exclusion assay, a significant cell death was observed in all prostate cancer cell lines except DU145 but not in non-malignant (RWPE-1 and BPH1) cells. Further analyses revealed that Alternol-induced cell death was an apoptotic response in a dose- and time-dependent manner, as evidenced by the appearance of apoptosis hallmarks such as Caspase-3 processing and PARP cleavage. Interestingly, Alternol-induced cell death was completely abolished by reactive oxygen species (ROS) scavengers, N-acetylcysteine (N-Ac) and dihydrolipoic acid (DHLA). We also demonstrated that the pro-apoptotic Bax protein was activated after Alternol treatment and was critical for Alternol-induced apoptosis. Animal xenograft experiments in nude mice showed that Alternol treatment largely suppressed tumor growth of PC-3 xenografts but not Bax-null DU-145 xenografts in vivo. These data suggest that Alternol might serve as a novel anticancer agent for late stageprostate cancer patient.

PMID:

 24688053

[PubMed – as supplied by publisher]

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2.
Molecules. 2013 Aug 5;18(8):9382-96. doi: 10.3390/molecules18089382.

Reactive oxygen species mediate isoalantolactone-induced apoptosis in human prostate cancer cells.

Abstract

Isoalantolactone, a medicinal plant-derived natural compound, is known to induce apoptosis in various cancer cell lines. However, its effect on apoptosis in prostate cancer cells has not been addressed. Thus, we examined the effects of isoalantolactone on prostate cancer cells. It was found that isoalantolactone inhibits growth of both androgen-sensitive (LNCaP) as well as androgen-independent (PC3 and DU-145) prostate cancer cells in a dose-dependent manner. Furthermore, our results indicate that isoalantolactone-induced apoptosis in prostate cancer PC3 cells is associated with the generation of ROS and dissipation of mitochondrial membrane potential (Δψm). In addition, isoalantolactone triggers apoptosis in prostate cancer cells via up-regulation of Bax, down-regulation of Bcl-2, survivin, and significant activation of caspase-3. Isoalantolactone-induced apoptosis is markedly abrogated when the cells were pretreated with N-acetylcysteine (NAC), a specific ROS inhibitor, suggesting that the apoptosis-inducing effect of isoalantolactone in prostate cancer cells is mediated by reactive oxygen species. These findings indicate that isoalantolactone induces reactive oxygen species-dependent apoptosis in prostate cancer cells via a novel mechanism involving inhibition of survivin and provide the rationale for further in vivo and preclinical investigation of isoalantolactone against human prostate cancer.

PMID:

 23921797

[PubMed – indexed for MEDLINE]

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3.
Maturitas. 2013 Jun;75(2):125-30. doi: 10.1016/j.maturitas.2013.03.006. Epub 2013 Apr 6.

Dietary supplements and prostate cancer: a systematic review of double-blind, placebo-controlled randomised clinical trials.

Abstract

Dietary supplements are popular among patients with prostate cancer (PC). The objective of this systematic review was to critically examine double-blind, placebo-controlled randomised clinical trials (RCTs) of non-herbal dietary supplements and vitamins (NHDS) for evidence thatprostate specific antigen (PSA) levels were reduced in PC patients. Five databases were searched from their inception through December 2012 to identify studies that met our inclusion criteria. Methodological quality was independently assessed by two reviewers using the Cochrane tool. Eight RCTs met the eligibility criteria and were of high methodological quality. The following supplements were tested: isoflavones (genistein, daidzein, and glycitein), minerals (Se) or vitamins (vitamin D) or a combination of antioxidants, bioflavonoids, carotenoids, lycopenes, minerals (Se, Zn, Cu, and Mg), phytoestrogens, phytosterols, vitamins (B2, B6, B9, B12, C, and E), and other substances (CoQ10 and n-acetyl-l cysteine). Five RCTs reported no significant effects compared with placebo. Two RCTs reported that a combination of antioxidants, isoflavones, lycopenes, minerals, plant oestrogens and vitamins significantly decreased PSA levels compared with placebo. One RCT did not report differences in PSA levels between the groups. In conclusion, the hypothesis that dietary supplements are effective treatments for PC patients is not supported by sound clinical evidence. There are promising data for only two specific remedies, which contained a mixture of ingredients, but even for these supplements, additional high quality evidence is necessary before firm recommendations would be justified.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

PMID:

 23567264

[PubMed – indexed for MEDLINE]

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4.
J Med Assoc Thai. 2012 Dec;95 Suppl 12:S56-62.

Antimetastatic potential of N-acetylcysteine on human prostate cancer cells.

Abstract

OBJECTIVE:

N-acetylcysteine (NAC), is one of the cheapest, safest and widely used over-the-counter-drugs in Thailand. Here the authors examine the antimetastatic potential of NAC on the metastasis of human prostate cancer cells.

MATERIAL AND METHOD:

Cytotoxicity of NAC to human prostate cancer cells, DU145 and PC3, were determined by proliferation assay using the 3-(4, 5-dimethylthiazol, 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) reagent. Cell migration and invasion were assessed by using a chemotaxis chamber containing membrane pre-coated with collagen IV and Matrigel, respectively. Cell attachment onto the surface of the membrane coated with collagen IV was tested for its adhesion potentiality.

RESULTS:

NAC could inhibit the growth of DU145 and PC3 cells. Suppression of migration and invasion of both human prostrate cancer cells were observed. Cell attachment to the collagen IV-coated surface was obviously reduced. All inhibitions occurred in a dose-dependent fashion in both cell lines.

CONCLUSION:

NAC could have a high potential in attenuating the migration of the human prostate cancer cells from their primary site and their adhesion and invasion to the remote locations. Hence, NAC might suppress the growth of the primary and the secondary tumors. Our findings suggest that NAC had a high possibility to become an antimetastatic agent for testing in clinical trials. Then, NAC might be used clinically as an optional adjuvant therapeutic drug in addition to the conventional standard treatment of human prostate cancer, obtaining a better outcome with the least toxic and affordable substance.

PMID:

 23513466

[PubMed – indexed for MEDLINE]

5.
Mol Carcinog. 2013 Mar 8. doi: 10.1002/mc.22014. [Epub ahead of print]

Reactive oxygen species generation inhibits epithelial-mesenchymal transition and promotes growth arrest in prostate cancer cells.

Abstract

Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis. © 2013 Wiley Periodicals, Inc.

Copyright © 2013 Wiley Periodicals, Inc.

 

 

The Overlooked Compound That Saves Lives

By Julius Goepp, MD

Innovative Strategies to Combat Kidney Disease

N-acetyl Cysteine

For more than three decades, a safe, low-cost compound has provided millions of people relief from the coughing, wheezing, and thick phlegm associated with cold and flu. Of course, pharmaceutical companies long ago co-opted it for profit by incorporating it into various patented drugs.

The sad consequence is that most aging individuals have never heard of it. Even many doctorsremain unaware of its potential role as a frontline defense against some of today’s most deadly public health threats, including:

  • Acetaminophen toxicity and acute liver failure: the number one cause of acute liver failure in the United States.1
  • Influenza: whose victims are primarily aging individuals—three quarters of all flu-related deaths occur in the elderly.2
  • Chronic obstructive pulmonary disease: the fourth-leading cause of death in the United States (includes emphysema and chronic bronchitis).2
  • Helicobacter pylori: the bacterial culprit behind stomach ulcers, and a potentially lethalpathogen closely linked to malignant gastric cancer, the second most frequent cause of cancer death worldwide.3

Fortunately, renewed clinical interest in its broad-spectrum benefits is yielding fresh data on promising interventions for this safe, effective compound.

In this article, you will discover the latest research on N-acetyl cysteine (NAC), a readily available, inexpensive amino-acid derivative with four decades of scientific validation. You will learn of its role in restoring intracellular levels of one of the body’s most powerful antioxidant defenses, glutathione(GSH). You will also find out how 600-1,800 mg of NAC daily may act as an effective intervention against a constellation of chronic, degenerative diseases, including impaired glucose control and cancer.

An Underutilized Intervention

NAC is a slightly modified version of the sulfur-containing amino acid cysteine. When taken internally, NAC replenishes intracellular levels of the natural antioxidant glutathione (GSH), helping to restore cells’ ability to fight damage from reactive oxygen species (ROS).

NAC has been used in conventional medicine for more than 30 years, primarily as a mucolytic (mucous-thinner) inhaled to manage conditions such as cystic fibrosis, in which mucous is abnormally thick and tenacious. While there is little in the scientific literature to support its use as an inhalant, NAC administered in this form remains highly popular among experienced pulmonary speclialists.4,5

NAC given intravenously or orally, on the other hand, saves lives every year as a treatment for acute poisoning with acetaminophen-containing pain-relieving drugs. Acetaminophen is sold as Tylenol® and combined with other drugs to create analgesic compounds, including Vicodin® and Percocet®.6Overdoses with acetaminophen are the number one cause of acute liver failure in the United States.6-8 Too much acetaminophen overwhelms the body’s glutathione reserves, which creates widespread and irreversible liver damage. NAC quickly restores protective levels of glutathione, averting catastrophe.7

Beyond this particular application, NAC has remained a relatively obscure and poorly understood compound until quite recently. Scientists all over the world are now beginning to understand just how vital glutathione metabolism really is, and how many disease states involve glutathione deficiency.9 According to Stanford University’s Dr. Kondala R. Atkuri, “NAC has been used successfully to treat glutathione deficiency in a wide range of infections, genetic defects and metabolic disorders, including HIV infection and COPD. Over two-thirds of 46 placebo-controlled clinical trials with orally administered NAC have indicated beneficial effects of NAC measured either as trial endpoints or as general measures of improvement in quality of life and well-being of the patients.”9

Multitargeted Regulation of Gene Expression

Multitargeted Regulation of Gene Expression

Much of NAC’s beneficial activity derives from its capacity to modulate expression of genes for myriad signaling molecules in the inflammatory response.10-12 NAC inhibits expression of pro-inflammatory cytokines following exposure to bacterial cell components and infection with influenza A virus.13,14 NAC suppresses the “master signaling molecule” nuclear factor-kappaB (NF-kB), which in turn prevents activation of multiple inflammatory mediators.15,16 NAC also regulates the gene for COX-2, the enzyme that produces pain- and inflammation-inducing prostaglandins in a wide array of chronic conditions.17

NAC’s ability to replenish the intracellular glutathione supply and mitigate oxidative damage is a separate and equally powerful mechanism that affords protection against DNA damage and cancer development, even in smokers.18 NAC’s inhibition of inflammatory cytokine production is another mechanism credited with cancer reduction in various body tissues.19

Gene expression modifications induced by NAC may also help reduce the acute oxidant-provoked inflammatory response following exercise, making vigorous activity safer and even more beneficial.20 Finally, obesity-associated insulin resistance, which arises from production of inflammatory signaling molecules in fat cells, can be sharply mitigated by NAC through regulation of their genes.21,22

The recent explosion of scientific evidence for NAC’s multi-targeted health benefits is matched only by the willful ignorance of the mainstream medical community. Some even question its safety, despite nearly 40 years of use in a variety of clinical conditions, which have established the safety of this compound, even at very high doses and for long-term treatments.18 One study demonstrated the safety of 1,800 mg per day for 142 days, while another study demonstrated the safety of 2,800 mg per day for 3 months.23

Here is a selection of the most compelling information about NAC from the global scientific community—information that should convince even skeptical mainstream physicians.

WHAT YOU NEED TO KNOW: N-ACETYL CYSTEINE’S BROAD-SPECTRUM BENEFITS
  • Long relegated to infrequent use in unusual circumstances, the amino acid-derived compound N-acetyl cysteine (NAC) has drawn increased scientific attention.
  • NAC replenishes levels of the intracellular antioxidant glutathione (GSH), which is often deficient with advancing age and in chronic illness.
  • NAC also regulates expression of scores of genes in the pathways that link oxidative stress to inflammation.
  • These dual effects give NAC a unique role in the prevention and treatment of many common diseases, both acute and chronic.
  • NAC can protect against avian influenza and more common seasonal flu symptoms.
  • NAC reduces the frequency and duration of attacks of chronic obstructive pulmonary disease (COPD) and may slow the clinical course of idiopathic pulmonary fibrosis (IPF).
  • NAC protects tissues from the effects of exercise-induced oxidative stress, adding value and safety to your workout.
  • NAC improves insulin sensitivity in people with some of the most difficult-to-treat metabolic disorders.
  • NAC blocks cancer development at virtually every step in the process, and through multiple mechanisms, making it an important cancer chemopreventive agent.
  • NAC fights the stomach infection Helicobacter pylori on two fronts, inhibiting the organism’s growth while reducing production of inflammatory cytokines that can lead to gastritis and cancer.
  • Though most individuals gain benefits from 600-1,800 mg/day, clinical studies have found that doses of up to 2,000 mg/day are safe and effective. A recent study demonstrated the safety of 2,800 mg/day for 3 months in patients with COPD.23

Potent Influenza Protection

H5N1 influenza, or bird flu, is a lethal and potentially pandemic infection that produces the massive release of inflammatory mediators aptly called the “cytokine storm.”24 Other more common forms of influenza also act by triggering massive cytokine releases that inflame vulnerable lung tissue. In early 2010, it was discovered that NAC offers dual protection against bird flu. It inhibits both virus replication and expression of pro-inflammatory molecules in cells infected with H5N1 virus, holding out the promise of effective protection in the event of a global avian flu pandemic.13


Influenza is a complex disease with multiple targets, most notably inflicting damage to lung tissue through extreme oxidative stress and inducing genes for a large variety of inflammatory mediators.26,27 At the microscopic level the destruction is vivid. The influenza virus causes such intracellular turmoil that the term “cell boiling” has been used to describe the devastation.28 But pretreatment of cells with NAC significantly offsets these effects, reducing the oxidative and inflammatory burden within lung tissue through multiple mechanisms.26,28-30
NAC has also proven effective against seasonal influenza and flu-like illnesses. In a large study of older adults who took 600 mg twice daily for 6 months, only 25% of those experienced influenza-like episodes, compared with 79% in the placebo group.25 Even those with flu symptoms experienced a significant reduction in illness severity and length of time confined to bed. All subjects tolerated the treatment well. The study’s lead author, Dr. Silvio de Flora, commented that “Administration of N-acetyl cysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals.”25

NAC has now been shown to protect laboratory mice from lethal influenza infection, synergistically enhancing the effects of several common antiviral medications.31,32 And a nutrient mixture containing NAC, green tea extract, certain amino acids and micronutrients had powerful antiviral effects in cultured cells, rivaling those of prescription flu drugs such as amantadine and oseltamivir (Tamiflu®).33,34 The NAC-based mixture actually affected viral replication for a longer period than did the drugs.34

In the words of prolific medical theorist Mark F. McCarty, “The most foolproof way to promote survival in epidemics of potentially lethal influenza is to target… intracellular signaling pathways which promote viral propagation or lung inflammation.”30 McCarty goes on to cite NAC’s benefits as a multitargeted supplement with precisely those attributes. NAC at doses of 600 mg twice daily may significantly reduce the risk of a devastating bout of influenza.

NAC AND PULMONARY ARTERIAL HYPERTENSION: A REAL RISK?
N-acetyl cysteine (NAC) produces numerous beneficial effects in many human tissues both by supporting natural antioxidant systems and by favorably affecting expression of genes involved in the inflammatory response.A 2007 study in laboratory mice, however, has raised a theoretical concern that chronic NAC administration in those animals might produce a condition called pulmonary arterial hypertension.76 Here is a review of that study and some reassuring facts:

The Issue

Pulmonary arterial hypertension (PAH) is an elevation in blood pressure in the arteries leading from the heart to the lungs. It is one of the consequences of chronic hypoxia (lack of sufficient oxygen) that occurs in a number of chronic cardiovascular and pulmonary (lung) diseases. It also arises in people with obstructive sleep apnea.77-79 It is a rare condition, but when it occurs it can be difficult to detect and may be fatal if untreated.79 Its causes remain unclear, but they seem to involve signaling molecules produced during hypoxia; some of those molecules include those involved in detecting and responding to oxidative stress.80

The Concern

Scientists at the University of Virginia School of Medicine were studying the molecular signaling involved in hypoxia-related development of PAH when they observed what seemed to be a concerning finding: mice treated with NAC over periods of 3 weeks were developing PAH that mimicked the effects of chronic hypoxia.76 The scientists were not studying the effects of NAC itself; they were simply using it to measure other nitrogen-related transfer reactions in blood. And the doses they used correspond to a human dose of about 20 grams (20,000 mg) per day—far above any known supplement recommendation. Nevertheless, parts of their report were cited in one commentary as raising “the concern that chronic NAC therapy may induce similar vascular pathology in patients.”81

Is this a realistic concern, or is it a laboratory anomaly? Here’s the evidence to date.

The Evidence

The Virginia team’s mouse study was published in 2007. Now, nearly 3 years later, there has not been a single additional publication connecting NAC therapy with PAH in either animals or humans. In reality, a substantial amount of science both before and after the 2007 report suggests just the opposite—that NAC may be instrumental in reducing, not increasing, the oxidant-induced blood vessel changes that occur in PAH. Here are the highlights:

  • In one of the original animal studies demonstrating that oxidative stress contributes to development of PAH induced by hypoxia, NAC actually reduced the heart and lung changes that lead to PAH, in part by reducing toxic peroxide molecules.80
  • NAC, given before and at the beginning of experimental hypoxia, was effective at preventing PAH, including deadly heart muscle changes, in laboratory rats.82
  • NAC protects experimental animals’ lungs from the acute lung injury caused by a variety of mechanisms involving hypoxia, oxidant stress, and inflammation, through its joint antioxidant and anti-inflammatory actions.83,84
  • A study of human volunteers revealed that NAC supplements at 1,800 mg/day increasedthe healthy respiratory response to hypoxia,85 which normally declines strongly with age and may contribute to PAH.86 Although this study was cited by the Virginia group as supporting their concern about NAC inducing PAH, no such evidence is presented in the human study, and in fact the authors conclude that NAC treatment “may be useful for elderly subjects and for patients who have other conditions with an oxidative shift… such as coronary heart disease and malignant diseases.”85

The Recommendation

There have been no further publications supporting this one-time observation made in an animal model using doses 10-20 times those suggested for long-term human supplementation. No human study has uncovered any evidence for a similar effect in humans. By contrast, there have been numerous studies demonstrating human benefit from NAC supplementation at moderate doses (1,200-1,800 mg per day) over the course of nearly 4 decades. At this point the known benefits of NAC appear to outweigh any potential risks. As with all supplementation, people should communicate clearly with their healthcare providers about how supplements and medications might work jointly to influence their health.

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