N-acetyl-cysteine (NAC): good for some things but dangerous with cancer.
Jacob Schor ND, FABNO
February 20, 2011
This is the time of year that our patients start using n-acetyl-cysteine or, because no one can remember the full name, NAC, for short. It’s particularly useful for treating upper respiratory and lung infections; it thins the really thick mucous secretions whose viscosity is approaching rubber cement allowing easier expellation.
[SpellCheck doesn’t think ‘expellation’ is a word but I think most of you will comprehend what I meant.]
NAC is so effective at reducing nasal and bronchial congestion that according to one frequently quoted, now classic, study published in 1997, many people don’t even notice they are sick. De Flora et al enrolled 262 mostly older subjects and gave them either 600 mg of NAC twice a day or placebo for a 6-month period from fall until spring. Treatment with NAC significantly reduced flu-like episodes. Yet at the end of the study similar percentages of treatment and placebo groups showed they had caught the flu when their blood antibodies were tested. Of those who tested positive for the flu, only 25% of the NAC takers reported noticing symptoms while 79% of those receiving the placebo group had been noticeably sick.
Over the last half dozen years or so a new use for NAC has appeared that is quite curious. Apparently it provides benefit for those suffering from obsessive-compulsive behaviors. A case report of a single patient with OCD who benefited from taking NAC was published in 2006. A 2007 paper reported on a trial using NAC to treat cocaine addicts and the patient responses “… appeared to favor higher doses of NAC (2400 mg/day and 3600 mg/day). The majority of subjects who completed the study (n=16) either terminated use of cocaine completely or significantly reduced their use of cocaine during treatment. Overall the findings suggest that it is feasible to treat cocaine-dependent treatment seekers with N-acetylcysteine…”
In another paper published in 2007, researchers from the University of Minnesota reported that NAC was useful in treating a specific form of OCD, compulsive gambling. Significant decreases in psychological profiles during treatment suggest that NAC was beneficial in this specific subgroup.
A 2009 paper reported on a double blinded placebo controlled trial that involved fifty individuals suffering from trichotillomania, that is compulsive hair pulling, and concluded that NAC supplementation produced, “… statistically significant reductions in trichotillomania symptoms.”
That’s the good news about NAC. The bad news is that I still often dissuade certain patients from taking it. Not because taking NAC causes any adverse symptoms, it doesn’t, but because it may interfere with cancer therapy.
Many of you may not know this but the majority of my patients have or had cancer. Over the last dozen or so years, the focus of my practice has shifted. It’s been quite a few years since I became a member of a specialty society of naturopathic doctors who focus on cancer, the Oncology Association of Naturopathic Physicians. Some years back, I was elected to their board of directors, serving terms as secretary, then vice-president and currently president. I am a recognized Fellow or the American Board of Naturopathic Oncologists. That is why, when I remember, I add their designation FABNO after my name.
Because of all this, I pay a great deal of attention as to how supplements will affect cancer cells.
N-acetyl-cysteine really worries me with cancer.
NAC is the precursor to a chemical called glutathione. Oral NAC is rapidly taken up by the body and quickly converted to glutathione.
Glutathione is the primary antioxidant within all of our cells. It protects our cells from oxidative damage. This is a good thing in healthy cells; we prefer that they are not damaged. But in cancer cells we prefer the opposite. We want cancer cells to be extra vulnerable to damage. Cancer cells generate oxidative chemicals referred to in total as reactive oxygen species (ROS) in an attempt to destroy themselves. Glutathione acts as a brake and prevents them from self-destruction or to use the scientific term, apoptosis.
Raising glutathione stops cancer cell death.
Most cancer therapies work to kill cancer cells by increasing the levels of reactive oxygen species within the cancer cells. This includes radiation therapy, most chemotherapies and most natural therapies.
Providing cancer cells with NAC, because it will increase glutathione, protects the cancer cells and prevents them from dying.
We often see NAC being used in studies investigating the mechanisms of how anticancer agents work; they use NAC in a simple trick to see if the drugs are killing cancer cells through the common mechanism of increasing reactive oxygen species. If adding NAC stops the action of the anticancer agent, than it is assumed it was acting through oxidative action. Let me find a recent example.
In April 2010, Korean researchers reported on the action of NAC in combination with a proteosome inhibiting chemotherapy drug known as MG132.
First they showed that MG132 increased the amounts of ROS in lung cancer cells and as expected, the drug slowed the rate of growth of the cancer cells. Then they treated the cancer cells with NAC. The drug no longer slowed growth rates.
The procedures followed in this study were not novel. They are routine when evaluating chemotherapy drugs. First, measure how well the drug works against tumor cells and then measure whether NAC stops the effect. This tells the scientists to what degree the drug’s action is via reactive oxygen species generation and whether other anti-cancer mechanisms are involved.
It’s not just the medical treatments that NAC will potentially interfere with. A paper from December 2010 tells us that NAC ‘blocked the antiproliferative’ effect of curcumin, that is stopped it from hindering the growth of cancer cells.
A paper scheduled for publication this coming April tells a similar story in regard to a traditional Chinese medicine known as “Cantharidin”.
A paper from last week on gingseng reports NAC has a similar benefit blocking action against cancer.
Same story with berberine. Same story actually with pretty much any natural treatment you might consider using along with the medical treatments. Most act through increasing ROS and NAC cancels that effect out.
Selenium stimulates apoptosis by generating ROS. Once again NAC inhibits the process.
Melatonin is the same. Even though we may describe melatonin as an antioxidant, in cancer cells it has the opposite effect and stimulates production of ROS. A January 2011 article reviewing melatonin’s effects describes again how NAC decreases the antitumor effect, in this particular study, against hematopoietic cancer cell lines.
There is no need to mention every last substance, you should be getting the idea by now, but let’s at least reference studies regarding a few more common anticancer agents.
Add vitamin D-3 to the list of things that lose their anticancer effect when combined with NAC. So too, green tea; “By treating cells with high concentrations of the reactive oxygen species (ROS) scavenger NAC (N-acetyl-1-cysteine), the apoptotic effect of EGCG [green tea] was abolished…”
Given information like this, it is remarkable that we still see some practitioners giving NAC to cancer patients. There is a reason for this. In the late 1980s, before the chemistry of apoptosis was well understood, it was noticed that NAC decreased the toxicity of some types of chemotherapy, especially the ones that rely on oxidative damage to kill cancer cells. No one at the time knew better and decreasing the suffering patients endured during treatment seemed like a reasonable course of action. But that was years ago and everyone should know better by now.
When we see cancer patients who are taking NAC, we try and find tactful words with which to dissuade them from the practice. We also attempt to dissuade cancer patients from consuming large amounts of whey protein. Whey is a great source of l-glutamine and can aid patients in rebuilding lost muscle mass. It is also a great source of l-cysteine and so also increases glutathione production. Again, because it increases glutathione, it may inactivate anticancer therapies. This connection is less well documented but still concerns us.
So, while NAC is great for a winter cold and potentially useful for treating compulsive behavior, it is something all cancer patients should stay far away from.
Eur Respir J. 1997 Jul;10(7):1535-41.
Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment.
De Flora S, Grassi C, Carati L.
Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.
N-acetylcysteine (NAC), an analogue and precursor of reduced glutathione, has been in clinical use for more than 30 yrs as a mucolytic drug. It has also been proposed for and/or used in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress, in general. The objective of the present study was to evaluate the effect of long-term treatment with NAC on influenza and influenza-like episodes. A total of 262 subjects of both sexes (78% > or = 65 yrs, and 62% suffering from nonrespiratory chronic degenerative diseases) were enrolled in a randomized, double-blind trial involving 20 Italian Centres. They were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 months. Patients suffering from chronic respiratory diseases were not eligible, to avoid possible confounding by an effect of NAC on respiratory symptoms. NAC treatment was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, versus 79% in the placebo group. Evaluation of cell-mediated immunity showed a progressive, significant shift from anergy to normoergy following NAC treatment. Administration of N-acetylcysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease.
PMID: 9230243 [PubMed - indexed for MEDLINE]Free Article
Psychopharmacology (Berl). 2006 Jan;184(2):254-6. Epub 2005 Dec 22.
N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.
Lafleur DL, Pittenger C, Kelmendi B, Gardner T, Wasylink S, Malison RT, Sanacora G, Krystal JH, Coric V.
RATIONALE: Dysfunction of glutamatergic neurotransmission has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and recent clinical reports suggest that some glutamate modulating agents are efficacious in the treatment of this disorder. N-acetylcysteine (NAC) is a readily available amino acid compound that is thought to attenuate glutamatergic neurotransmission. NAC may be useful in treating psychiatric disorders involving glutamatergic dysfunction such as OCD.
OBJECTIVES: To examine the efficacy of augmentation with NAC in a patient with serotonin reuptake inhibitor (SRI)-refractory OCD.
METHODS: A patient with SRI-refractory OCD was treated with an off-label use of NAC augmentation of fluvoxamine over several weeks.
RESULTS: NAC augmentation of fluvoxamine resulted in a marked decrease in Yale-Brown Obsessive Compulsive Scale (Y-BBOCS) score and a clinically significant improvement in OCD symptoms.
CONCLUSIONS: NAC augmentation was effective in treating SRI-refractory OCD in this single case. Further research is warranted to investigate the use of NAC and other glutamate modulating agents in the treatment of OCD.
PMID: 16374600 [PubMed - indexed for MEDLINE]
Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):389-94. Epub 2006 Nov 17.
An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study.
Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ.
Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, Charleston, SC 29425, USA. firstname.lastname@example.org
Recent preclinical studies implicate N-acetylcysteine (NAC), a cysteine prodrug, as a potential medication for preventing relapse to cocaine use; however, little is known about the safety and tolerability of NAC in cocaine-dependent subjects in an outpatient setting. This pilot study examines the safety and tolerability of 3 doses of NAC for the treatment of cocaine dependence. Twenty three treatment-seeking cocaine-dependent patients participated in a 4-week medication trial and received NAC at doses of 1200 mg/day, 2400 mg/day or 3600 mg/day. Results suggested that the three doses were well tolerated. Overall, the retention rates appeared to favor higher doses of NAC (2400 mg/day and 3600 mg/day). The majority of subjects who completed the study (n=16) either terminated use of cocaine completely or significantly reduced their use of cocaine during treatment. Overall the findings suggest that it is feasible to treat cocaine-dependent treatment seekers with N-acetylcysteine on an outpatient basis.
Biol Psychiatry. 2007 Sep 15;62(6):652-7. Epub 2007 Apr 18.
N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study.
Grant JE, Kim SW, Odlaug BL.
Department of Psychiatry, University of Minnesota School of Medicine, 2450 Riverside Avenue, Minneapolis, MN 55454, USA. email@example.com
BACKGROUND: Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. N-acetyl cysteine (NAC), an amino acid, seems to restore extracellular glutamate concentration in the nucleus accumbens and therefore offers promise in reducing addictive behavior.
METHODS: Twenty-seven subjects (12 women) with DSM-IV PG were treated in an 8-week open-label trial of NAC with responders (defined as a > or = 30% reduction in Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score at end point) randomized to 6 weeks of double-blind NAC or placebo.
RESULTS: The PG-YBOCS scores decreased from a mean of 20.3 +/- 4.1 at baseline to 11.8 +/- 9.8 at the end of the open-label phase (p < .001). Sixteen of 27 subjects (59.3%) met responder criteria. The mean effective dose of NAC was 1476.9 +/- 311.3 mg/day. Of 16 responders, 13 entered the double-blind phase. Of those assigned to NAC, 83.3% still met responder criteria at the end of the double-blind phase, compared with only 28.6% of those assigned to placebo.
CONCLUSIONS: The efficacy of NAC lends support to the hypothesis that pharmacological manipulation of the glutamate system might target core symptoms of reward-seeking addictive behaviors such as gambling. Larger, longer, placebo-controlled double-blind studies are warranted.
PMID: 17445781 [PubMed - indexed for MEDLINE]
Arch Gen Psychiatry. 2009 Jul;66(7):756-63.
N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study.
Grant JE, Odlaug BL, Kim SW.
Department of Psychiatry, University of Minnesota School of Medicine, Minneapolis, MN 55454, USA. firstname.lastname@example.org
CONTEXT: Trichotillomania is characterized by repetitive hair pulling that causes noticeable hair loss. Data on the pharmacologic treatment of trichotillomania are limited to conflicting studies of serotonergic medications. N-acetylcysteine, an amino acid, seems to restore the extracellular glutamate concentration in the nucleus accumbens and, therefore, offers promise in the reduction of compulsive behavior.
OBJECTIVE: To determine the efficacy and tolerability of N-acetylcysteine in adults with trichotillomania.
DESIGN: Twelve-week, double-blind, placebo-controlled trial.
SETTING: Ambulatory care center.
PATIENTS: Fifty individuals with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years).
INTERVENTIONS: N-acetylcysteine (dosing range, 1200-2400 mg/d) or placebo was administered for 12 weeks.
MAIN OUTCOME MEASURES: Patients were assessed using the Massachusetts General Hospital Hair Pulling Scale, the Clinical Global Impression scale, the Psychiatric Institute Trichotillomania Scale, and measures of depression, anxiety, and psychosocial functioning. Outcomes were examined using analysis of variance modeling analyses and linear regression in an intention-to-treat population.
RESULTS: Patients assigned to receive N-acetylcysteine had significantly greater reductions in hair-pulling symptoms as measured using the Massachusetts General Hospital Hair Pulling Scale (P < .001) and the Psychiatric Institute Trichotillomania Scale (P = .001). Fifty-six percent of patients "much or very much improved" with N-acetylcysteine use compared with 16% taking placebo (P = .003). Significant improvement was initially noted after 9 weeks of treatment.
CONCLUSIONS: This study, the first to our knowledge that examines the efficacy of a glutamatergic agent in the treatment of trichotillomania, found that N-acetylcysteine demonstrated statistically significant reductions in trichotillomania symptoms. No adverse events occurred in the N-acetylcysteine group, and N-acetylcysteine was well tolerated. Pharmacologic modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00354770.
Int J Mol Med. 2010 Apr;25(4):657-62.
The effects of N-acetyl cysteine on the MG132 proteasome inhibitor-treated lung cancer cells in relation to cell growth, reactive oxygen species and glutathione.
Han YH, Moon HJ, You BR, Kim SZ, Kim SH, Park WH.
Department of Physiology, Medical School, Centers for Healthcare Technology Development Institutefor Medical Sciences, Chonbuk National University, JeonJu 561-180, Republic of Korea.
MG132 as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). Here, we investigated the effects of N-acetyl cysteine (NAC; a well-known antioxidant), L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) or diethyldithiocarbamate (DDC; an inhibitor of Cu/Zn-SOD) on MG132-treated Calu-6 or A549 lung cancer cells in relation to cell growth, ROS and GSH levels. MG132 inhibited the growth of Calu-6 and A549 cells at 24 h. MG132 induced apoptosis in both cell lines, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim). ROS levels including O(2)(.-) were increased in both MG132-treated lung cells. MG132 also induced GSH depletion in both lung cell types. Treatment with 10 microM BSO or 1 microM DDC affected ROS and GSH levels in MG132-treated Calu-6 cells. However, these changes did not influence cell growth and death in the cells. NAC prevented cell growth inhibition and death in MG132-treated lung cells, which was accompanied by decreased ROS, but not by decreased GSH depletion. In conclusion, the changes of ROS and GSH by MG132, NAC, BSO or DDC were partially related to cell growth and death in the lung cancer cell lines Calu-6 and A549.
Korean J Physiol Pharmacol. 2010 Dec;14(6):391-7. Epub 2010 Dec 31.
Curcumin Induces Downregulation of E2F4 Expression and Apoptotic Cell Death in HCT116 Human Colon Cancer Cells; Involvement of Reactive Oxygen Species.
Kim KC, Lee C.
Department of Internal Medicine, College of Medicine, Catholic University of Daegu, Daegu 705-718, Korea.
E2F transcription factors and their target genes have been known to play an important role in cell growth control. We found that curcumin, a polyphenolic phytochemical isolated from the plant Curcuma longa, markedly suppressed E2F4 expression in HCT116 colon cancer cells. Hydrogen peroxide was also found to decrease E2F4 protein level, indicating the involvement of reactive oxygen species (ROS) in curucmin-induced downregulation of E2F4 expression. Involvement of ROS in E2F4 downregulation in response to curcumin was confirmed by the result that pretreatment of cells with N-acetylcystein (NAC) before exposure of curcumin almost completely blocked the reduction of E2F4 expression at the protein as well as mRNA level. Anti-proliferative effect of curcumin was also suppressed by NAC which is consistent to previous reports showing curcumin-superoxide production and induction of poly (ADP-ribose) polymerase (PARP) cleavage as well as apoptosis. Expression of several genes, cyclin A, p21, and p27, which has been shown to be regulated in E2F4-dependent manner and involved in the cell cycle progression was also affected by curcumin. Moreover, decreased (cyclin A) and increased (p21 and p27) expression of these E2F4 downstream genes by curcumin was restored by pretreatment of cells with NAC and E2F4 overexpression which is induced by doxycycline. In addition, E2F4 overexpression was observed to partially ameliorate curcumin-induced growth inhibition by cell viability assay. Taken together, we found curcumin-induced ROS down-regulation of E2F4 expression and modulation of E2F4 target genes which finally lead to the apoptotic cell death in HCT116 colon cancer cells, suggesting that E2F4 appears to be a novel determinant of curcumin-induced cytotoxicity.
PMID: 21311680 [PubMed - in process]
Int J Oncol. 2011 Apr;38(4):1067-73. doi: 10.3892/ijo.2011.922. Epub 2011 Jan 24.
Cantharidin induces G2/M phase arrest and apoptosis in human colorectal cancer colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways.
Huang WW, Ko SW, Tsai HY, Chung JG, Chiang JH, Chen KT, Chen YC, Chen HY, Chen YF, Yang JS.
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, R.O.C.
Cantharidin (CTD) is a traditional Chinese medicine and an effective component isolated from blister beetle, and it has been demonstrated to have anticancer, antibiotic, antivirus activities and immune-regulated functions. It has been reported that CTD induces cell cycle arrest and apoptosis in many cancer cell types. However, there are no reports showing that CTD would induce cell cycle arrest and apoptosis in human colorectal cancer colo 205 cells. In this study, we studied colo 205 cells which were treated with CTD and demonstrated its molecular mechanisms in apoptosis. CTD induced growth inhibition, G2/M phase arrest and apoptosis in colo 205 cells. The IC50 is 20.53 µM in CTD-treated colo 205 cells. DAPI/TUNEL double staining and Annexin V assays were used to confirm the apoptotic cell death in colo 205 cells after CTD exposure. CTD caused G2/M arrest, down-regulated CDK1 activity, decreased Cyclin A, Cyclin B, CDK1 and increased CHK1 and p21 protein levels. Colorimetric assays also indicated that CTD triggered activities of casapse-8, -9 and -3 in colo 205 cells. Moreover, CTD increased ROS production and decreased the level of mitochondrial membrane potential (ΔΨm) in colo 205 cells. Consequently, CTD-induced growth inhibition was significantly attenuated by N-acetylcysteine (NAC, a scavenger). CTD stimulated the protein levels of Fas/CD95, the caspase-3 active form, cytochrome c and Bax, but suppressed the protein levels of pro-caspase-8, pro-caspase-9 and Bcl-2, determined by Western blot analysis. Based on our observations, we suggest that CTD is able to induce G2/M phase arrest and apoptosis in colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways.
Cancer Lett. 2011 Feb 28;301(2):185-92. Epub 2010 Dec 30.
Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53.
Li B, Zhao J, Wang CZ, Searle J, He TC, Yuan CS, Du W.
Ben May Department for Cancer Research, The University of Chicago, IL 60637, United States.
Ginsenosides are the main bioactive components in American ginseng, a commonly used herb. In this study, we showed that the ginsenoside Rh2 exhibited significantly more potent cell death activity than the ginsenoside Rg3 in HCT116 and SW480 colorectal cancer cells. Cell death induced by Rh2 is mediated in part by the caspase-dependent apoptosis and in part by the caspase-independent paraptosis, a type of cell death that is characterized by the accumulation of cytoplasmic vacuoles. Treatment of cells with Rh2 activated the p53 pathway and significantly increased the levels of the pro-apoptotic regulator, Bax, while decreasing the levels of anti-apoptosis regulator Bcl-2. Removal of p53 significantly blocked Rh2-induced cell death as well as vacuole formation, suggesting that both types of cell death induced by Rh2 are mediated by p53 activity. Furthermore, we show that Rh2 increased ROS levels and activated the NF-κB survival pathway. Blockage of ROS by NAC or catalase inhibited the activation of NF-κB signaling and enhanced Rh2-induced cell death, suggesting that the anti-cancer effect of Rh2 can be enhanced by antioxidants.
Int J Oncol. 2011 Feb;38(2):485-92. doi: 10.3892/ijo.2010.878. Epub 2010 Dec 17.
Berberine sensitizes TRAIL-induced apoptosis through proteasome-mediated downregulation of c-FLIP and Mcl-1 proteins.
Lee SJ, Noh HJ, Sung EG, Song IH, Kim JY, Kwon TK, Lee TJ.
Department of Anatomy, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong Nam-Gu, Daegu 705-717, Republic of Korea.
Berberine (BBR) is an isoquinoline alkaloid which has a wide spectrum of clinical applications including anti-tumor, anti-microbial and anti-inflammatory activities. In this study, we showed that co-treatment with subtoxic doses of BBR and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis in human renal cancer cells, Caki cells, but not in normal tubular kidney cells. Treatment of Caki cells with BBR resulted in downregulation of c-FLIP and Mcl-1 proteins in a dose-dependent manner. The BBR-induced downregulation of c-FLIP and Mcl-1 proteins were involved in proteasome dependent pathways, which was confirmed by the result that pre-treatment with the proteasome inhibitor MG132 inhibited berberine-induced downregulation of the c-FLIP and Mcl-1 proteins. Pretreatment with N-acetyl-L-cysteine (NAC) significantly inhibited the cell death induced by the combined treatment with BBR and TRAIL as well as recovered the expression levels of c-FLIP and Mcl-1 downregulated by treatment with BBR. These results suggested that BBR-stimulated TRAIL-induced apoptosis is dependent on the generation of reactive oxygen species through the downregulation of c-FLIP and Mcl-1 proteins. In conclusion, this study demonstrates that BBR enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated c-FLIP and Mcl-1 down-regulation.
Zhao R et al: Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells. Cancer Res. 2006 Feb 15;66(4):2296-304.
J Trace Elem Med Biol. 2003;17(1):19-26.
Induction of apoptosis by sodium selenite in human acute promyelocytic leukemia NB4 cells: involvement of oxidative stress and mitochondria.
Li J, Zuo L, Shen T, Xu CM, Zhang ZN.
Hematology department, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Peking, China. email@example.com
The mechanisms involved in the anti-carcinogenic activity of selenium remained to be elucidated. In the present study, we examined sodium selenite induced apoptosis and oxidative stress in human acute promyelocytic leukemia cell lines (NB4). Cell growth and viability were assessed by trypan blue exclusion and cell counting; apoptosis by DNA electrophoresis and analysis of intracellular DNA contents; reactive oxygen species and reduced glutathione in the cell were measured by lucigenin dependent chemoluminescent (CL) test and spectrophotometer; mitochondrial transmembrane potential was measured by flow cytometry. Sodium selenite could inhibit the growth and induce apoptosis of NB4 cells. Sodium selenite could increase the production of reactive oxygen species (ROS) in NB4 cells and decrease the level of intracellular reduced glutathione, but caused no change in the activity of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx). Sodium selenite enhanced the collapse of mitochondrial transmembrane potential (MTP), in parallel with the production of ROS. Finally antioxidant N-acetylcysteine (NAC) could inhibit the ROS production, MTP collapse and apoptosis in NB4 cells. Our results suggested that sodium selenite could induce apoptosis of NB4 cells through mitochondrial change mediated by production of reactive oxygen species within the cells.
PMID: 12755497 [PubMed - indexed for MEDLINE]
Buyukavci M et al: Melatonin cytotoxicity in human leukemia cells: relation with its pro-oxidant effect. Fundam Clin Pharmacol. 2006 Feb;20(1):73-9.)
Medina-Navarro R et al: Pro-oxidating properties of melatonin in the in vitro interaction with the singlet oxygen. Endocr Res. 1999 Aug-Nov;25(3-4):263-80.
Basic Clin Pharmacol Toxicol. 2011 Jan;108(1):14-20. doi: 10.1111/j.1742-7843.2010.00619.x.
Pro-oxidant effect of melatonin in tumour leucocytes: relation with its cytotoxic and pro-apoptotic effects.
Bejarano I, Espino J, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB.
Department of Physiology, Neuroimmunophysiology and Chrononutrition Research Group, University of Extremadura, Badajoz, Spain.
Melatonin has many effects on a wide range of physiological functions and is involved in a number of pathological events including oncostatic and neoplastic processes. The tissue protective actions of melatonin are attributed to its well-known antioxidant activity though melatonin might also exert pro-oxidant effects, particularly in tumour cells. This study evaluated the pro-oxidant effects of melatonin in tumour cell lines of human haematopoietic origin. Melatonin treatment is able to stimulate production of intracellular reactive oxygen species (ROS), as revealed by the increase in rhodamine-123 fluorescence, which was associated with significant cytotoxicity and activation of caspase activities. Furthermore, pre-treatment of cells with well-known antioxidants, such as N-acetyl-L-cysteine (NAC), trolox, PEG-catalase and reduced glutathione (GSH), reversed the effects of melatonin on both intracellular ROS production, as on the cytotoxicity and caspase activation. This pro-oxidant action of melatonin may assist in limiting tumour cell growth.
© 2010 The Authors. Basic & Clinical Pharmacology & Toxicology © 2010 Nordic Pharmacological Society.
J Steroid Biochem Mol Biol. 2011 Jan;123(1-2):85-9. Epub 2010 Nov 24.
Vitamin D metabolites and analogs induce lipoxygenase mRNA expression and activity as well as reactive oxygen species (ROS) production in human bone cell line.
Somjen D, Katzburg S, Grafi-Cohen M, Knoll E, Sharon O, Posner GH.
Institute of Endocrinology, Metabolism and Hypertension Tel-Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
Vitamin D metabolites and its less-calcemic analogs (vitamin D compounds) are beneficial for bone and modulate cell growth and energy metabolism. We now analyze whether 25(OH)D(3) (25D), 1,25(OH)(2)D(3) (1,25D), 24,25(OH)(2)D(3) (24,25D), JKF1624F(2)-2 (JKF) or QW1624F(2)-2 (QW) regulate lipooxygenase (LO) mRNA expression and its products; hydroxyl-eicosatetraenoic acid (12 and 15HETE) formation, as well as reactive oxygen species (ROS) production in human bone cell line (SaOS2) and their interplay with modulation of cell proliferation and energy metabolism. All compounds except 25D increased 12LO mRNA expression and modulated 12 and 15HETE production whereas ROS production was increased by all compounds, and inhibited by NADPH oxidase inhibitors diphenyleneiodonium (DPI) and N-acetylcysteine (NAc). Baicaleine (baic) the inhibitor of 12 and 15LO activity blocked only slightly the stimulation of DNA synthesis by all compounds, whereas DPI inhibited almost completely the stimulation of DNA and CK by all compounds. Treatments of cells with 12 or 15HETE increased DNA synthesis and CK that were only slightly inhibited by DPI. These results indicate that vitamin D compounds increased oxidative stress in osteoblasts in part via induction of LO expression and activity. The increased ROS production mediates partially elevated cell proliferation and energy metabolism, whereas the LO mediation is not essential. This new feature of vitamin D compounds is mediated by intracellular and/or membranal binding sites and its potential hazard could lead to damage due to increased lipid oxidation, although the transient mediation of ROS in cell proliferation is beneficial to bone growth in a yet unknown mechanism
Ann N Y Acad Sci. 2009 Aug;1171:538-44.
Green tea catechin controls apoptosis in colon cancer cells by attenuation of H2O2-stimulated COX-2 expression via the AMPK signaling pathway at low-dose H2O2.
Park IJ, Lee YK, Hwang JT, Kwon DY, Ha J, Park OJ.
Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul, Korea.
This study investigated the apoptotic regulation by green tea catechin epigallcatechin-3-gallate (EGCG) on colon cancer cells in the presence of low-dose H(2)O(2) known to exert the activation of signal pathways leading to cell proliferation. In the presence of low-dose H(2)O(2), EGCG induced apoptosis and abolished the cell-proliferative effect exhibited by low-dose H(2)O(2). This reduction of growth was accompanied by an activation of AMP-activated kinase (AMPK), a decrease in cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) levels, and the induction of apoptotic markers such as p53 and poly(ADP-ribose) polymerase (PARP) cleavage. The low-dose H(2)O(2) stimulated COX-2 expression, and treating cells with synthetic AMPK activator AICAR (5-aminoimiazole-4-carboxamide-1-beta-d-ribofuranoside) resulted in greater suppression of COX-2 expression and PGE(2). By treating cells with high concentrations of the reactive oxygen species (ROS) scavenger NAC (N-acetyl-1-cysteine), the apoptotic effect of EGCG was abolished and led to suppression of AMPK and COX-2, indicating that the liberation of excessive ROS might be the upstream signal of the AMPK-COX-2 signaling pathway even in the presence of low-dose H(2)O(2).