Antabuse Against Cancer

The drug Antabuse (disulfram), used as part of alcohol aversion has anticancer properties, with mechanisms described in this paper. Abstract:

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

More Dangers Of Alcohol

The dangers of alcohol consumption is underscored by changes in gene expression observed in alcoholic steatohepatitis.  Lifestyle factors do in fact alter us at the cellular and molecular level, sometimes to our benefit and sometimes to our detriment.  Abstract:

Hepatic progenitor cells (HPCs) are small cells with a relative large oval nucleus and a scanty cytoplasm situated in the canals of Hering that express markers of (immature) hepatocytes and cholangiocytes. HPCs are present in large numbers in alcoholic steatohepatitis (ASH), one of the leading causes of chronic liver disease. To date, the mechanisms responsible for proliferation and differentiation of human HPCs are still poorly understood and the role of HPCs in ASH development is unknown. In this study, we aimed to characterise human HPCs and their interactions with other cells through comparison, on both protein and RNA level, of HPC-enriched cell populations from adult human liver tissue using different isolation methods. Fresh human liver tissue was collected from ASH explant livers and HPC-enriched cell populations were obtained via four different isolation methods: side population (SP), epithelial cell adhesion molecule (EpCAM) and trophoblast antigen 2 (TROP-2) membrane marker isolation and laser capture microdissection. Gene expression profiles of fluorescent-activated cell-sorted HPCs, whole liver extracts and laser microdissected HPC niches were determined by RNA-sequencing. Immunohistochemical evaluation of the isolated populations indicated the enrichment of HPCs in the SP, EpCAM+ and TROP-2+ cell populations. Pathway analysis of the transcription profiles of human HPCs showed an enrichment and activation of known HPC pathways like Wnt/β-catenin, TWEAK and HGF. Integration of the HPC niche profile suggests autocrine signalling by HPCs (TNFα, PDGFB and VEGFA) as well as paracrine signalling from the surrounding niche cells including MIF and IGF-1. In addition, we identified IL-17 A signalling as a potentially novel pathway in HPC biology. In conclusion, we provide the first RNA-seq-based, comparative transcriptome analysis of isolated human HPCs from ASH patients and revealed active signalling between HPCs and their surrounding niche cells in ASH livers and suggest that HPCs can actively contribute to liver inflammation.

Zero Alcohol Listerine

I’ve switched from using regular Listerine to the Zero Alcohol version.  Given the possible links between alcohol and oral cancer, I thought it prudent.  However, note that there is no evidence linking alcohol-containing mouthwash and oral cancer, at least according to this study, abstract:

BACKGROUND:

Use of mouthwash and an increased risk of oral cancer has been a source of controversy for decades. A meta-analysis of epidemiological studies of mouthwash and oral cancer and, specifically, mouthwash containing >25% alcohol, was undertaken.

METHODS:

Summary estimates were obtained with maximum likelihood estimates from random effects models. Sensitivity analyses were conducted to evaluate the influence of various inclusion.

RESULTS:

Eighteen studies were included in the meta-analysis. There was no statistically significant associations found between regular use of mouthwash and risk of oral cancer (RR=1.13; 95% CI (0.95-1.35)). There was no significant trend in risk of oral cancer associated with increased daily usage of mouthwash (p=0.11). There was no association between reported use of mouthwash specifically containing alcohol and risk of oral cancer (RR=1.16; 95% CI (0.44, 3.08)).

CONCLUSIONS:

This quantitative analysis of mouthwash use and oral malignancy revealed no statistically significant associations between mouthwash use and risk of oral cancer, nor any significant trend in risk with increasing daily use; and no association between use of mouthwash containing alcohol and oral cancer risk.

But, still, why take the chance?  Studies are often refuted and overturned.  It happens all the time.  My view is, if an alcohol-free version exists, why not use it?  Just playing the percentages, so to speak.  My understanding is that the alcohol-free version is just as effective as regular, so there’s no loss while you can play it safe – just in case a future study reverses the conclusion cited above. What have you got to use?  As to why use Listerine at all – I find it reduces the accumulation of tooth plaque, likely by controlling the numbers of mouth bacteria.

Chickens And Fetal Alcohol Syndrome

Mice are not the only animal model used to study human disorders. Avian embryos, in the case the chicken, can be used as model to investigate fetal alcohol syndrome, a devastating disorder that occurs wen pregnant women ignore the injunction against drinking alcohol.  These model organisms can be used to determine mechanisms by which alcohol does its damage, stressing cell signaling pathways, with the eventual hope of better dealing with the effects of this disorder.  Of course, the best therapy here, as with almost all disorders, is prevention.  Don't drink alcohol when pregnant.  Abstract:

Prenatal alcohol exposure (PAE) remains a leading preventable cause of structural birth defects and permanent neurodevelopmental disability. The chick (Gallus gallus domesticus) is a powerful embryological research model and was possibly the first (Fere, 1895) in which alcohol's teratogenicity was demonstrated. Pharmacologically relevant alcohol exposures in the range of 20-70 mM (20-80 mg/egg) disrupt chick embryo growth, morphogenesis, and behavior, and the resulting phenotypes strongly parallel those of mammalian models. The avian embryo's direct accessibility has enabled novel insights into alcohol's teratogenic mechanisms. These include the contribution of IGF1 signaling to growth suppression, the altered flow dynamics that reshape valvuloseptal morphogenesis and mediate its cardiac teratogenicity, and the suppression of Wnt and Shh signals to disrupt neural crest migration, expansion, and survival and underlie its characteristic craniofacial deficits. The genetic diversity within commercial avian strains enabled identification of unique loci, such as ribosome biogenesis, that modify vulnerability to alcohol. This venerable research model is equally relevant for the future, as the application of technological advances including CRISPR, optogenetics, and biophotonics to the embryo's ready accessibility creates a unique model in which investigators can manipulate and monitor the embryo in real-time to investigate alcohol's actions upon cell fate.

What's In The Wine?

Resveratrol, which is found in wine as well as in other foodstuffs, has been thought to have a number of positive health benefits.  Here is a study that shows some activity against bone cancer cells.  Certain signaling pathways are involved, including suppression of Wnt signaling. Abstract:

Osteosarcoma is a high-grade bone sarcoma with strong invasive ability. However, treatment with traditional chemotherapeutic drugs is limited by low tolerability and side effects. Resveratrol has been reported previously to have selective antitumor effect on various tumor cells while little is known about its effects and underlying mechanism in osteosarcoma biology. In this study, we found that resveratrol inhibits proliferation and glycolysis, induces apoptosis and reduces the invasiveness of U2-OS cells in vitro. After treatment with resveratrol, the expression of related Wnt/β-catenin signaling pathway target genes, such as β-catenin, c-myc, cyclin D1, MMP-2 and MMP-9, was downregulated and an increased E-cadherin level was observed as well. Additionally, the dual luciferase assay results also indicated that resveratrol suppressed the activity of Wnt/β-catenin signaling pathway. Interestingly, we noticed that the expression of connexin 43 (Cx43) increased with the prolongation of resveratrol treatment time. To further investigate the relationship between Cx43 and the Wnt/β-catenin signaling pathway in osteosarcoma, we used lentiviral-mediated shRNA to knockdown the expression of Cx43. Knockdown of Cx43 activated the Wnt/β-catenin signaling pathway, promoted proliferation and invasion, and inhibited apoptosis of U2-OS cells. Taken together, our results demonstrate that the antitumor activity of resveratrol against U2-OS cells in vitro occurs through up-regulating Cx43 and E-cadherin, and suppressing the Wnt/β-catenin signaling pathway. Moreover, Cx43 expression is negatively related to the activity of the Wnt/β-catenin pathway in U2-OS cells.

More On Cancer Prevention And Lifestyle

Here is recent news on yet another study linking lifestyle to cancer risk.  These are all things you, as a reader of this blog, should be well aware of by now.  The importance of curbing these behaviors to reduce cancer risk is underscored by these additional data.

Researchers with the American Cancer Society looked at data on cancer incidence and deaths, finding that 42 percent of all cancer cases in the United States -– and nearly half of all cancer deaths – are linked to preventable risk factors like cigarette smoking, exposure to secondhand smoke, excess body weight, alcohol intake and dietary choices.

Cigarette smoking, in particular, was connected to far more cancer cases and deaths than any other single risk factor, accounting for 19 percent of all cancer cases and 28.8 percent of deaths. Overweight and obesity came in second, responsible for 7.8 percent of cases and 6.5 percent of deaths, while alcohol intake was the third most important factor, leading to 5.6 percent of cancer cases and 4 percent of deaths.

Although there are some sex-specific differences as to the relative importance of various risk factors, the bottom line is that these things – smoking/overweight/obese, bad diets, certain STDs, alcohol – are bad for everyone.  Be aware and adjust your life accordingly, to the extent you are able.

Alcohol And Cancer

Even moderate alcohol consumption can increase the risk of cancer.

Consuming alcoholic beverages, even in moderation, may increase your risk of developing certain cancers, according to a new statement released by the American Society of Clinical Oncology (ASCO).

"People typically don't associate drinking beer, wine, and hard liquor with increasing their risk of developing cancer in their lifetimes," Dr. Bruce Johnson, president of the ASCO, an organization of cancer doctors, said in a statement.

Consuming just 1 alcoholic drink a day increases breast cancer risk, report finds…

…Ashton said that moderate alcohol consumption is defined as up to an average of one drink a day for women (or seven drinks per week) and two drinks a day for men (or 14 drinks a week). She added that this can also cause confusion because of the various types of alcohol available.

For wine, a standard serving size is considered to be 5 ounces. For beer, 12 ounces is considered a standard serving size. Meanwhile, for hard liquor, 1.5 ounces is considered a standard serving. Ashton adds that if you pour more than these standard serving sizes, it counts for more than one drink.

Ashton said alcohol consumption has been shown to be a causative factor in a wide range of cancers, including cancer of the head and neck, esophagus, breast and colon. It may also be associated with liver cancer, according to Ashton.

On the other hand, we are sometimes told about cardiovascular benefits to moderate wine consumption for example.  I’m not an alcohol drinker myself.  Listen to your doctor’s advice about this.

Error-Prone DNA Repair Targeted To Active Genes By Carcinogens

By Augustus Binu, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=41205743

Here is a paper that claims that carcinogens like tobacco, UV exposure, and alcohol consumption promote error-prone DNA repair targeted to active genes, therefore having a greater impact in promoting cancer by affecting those important genes.

Another reason to avoid those carcinogens.

Breast cancer risk

Decrease your risk of breast cancer by more than 30%. 

AICR tells you how.

Just do not follow the AICR recipes!

The Vices Of Men

By Vincent van Gogh - Scanned from Smoke: a global history of smoking (2004) ISBN 1-86189-200-4, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3857076

The paper linked here is a fascinating review that looks at three major vices of men – drinking alcohol, being overweight/obese, and smoking tobacco – and how these activities can damage male fertility and also negatively affect the health of their offspring. Mechanisms by which these vices can affect fertility and the health of children include epigenetic changes to sperm DNA and non-coding RNA (changes to the modification to DNA and RNA, not including actual sequence mutation, that can affect gene expression), sperm DNA damage (which can cause actual sequence mutation affecting gene expression), changes in sperm chromatin structure (for example, changes in the chromosome structure that can affect which genes are expressed and which are silenced), and changes in seminal plasma (that can affect the function of the sperm cells themselves).  Abstract:

There is growing evidence from animal and human studies that demonstrate that acquired paternal traits can impair both a male's fertility and the health of his offspring, including advanced age, smoking, stress, trauma, under-nutrition, infection, toxin exposure, and obesity. Curiously, many of these factors manifest as impaired neurological, behavioural, and/or metabolic functioning in offspring. The underlying molecular mechanisms that respond to the paternal environment and act as vectors of intergenerational transmission are beginning to emerge. This review focuses on three vices of men (alcohol consumption, overweight/obesity, and tobacco smoking) that damage fertility and pose risks to offspring health. These vices are not only the three most prevalent but are also leading risk factors for death and disability adjusted life years (DALYs) worldwide. Clearly, any epigenetic/genetic alterations induced by the paternal exposures responsible for transmission need to escape/bypass the substantial post-fertilisation reprogramming that occurs during embryo development. For example paternal obesity alters the molecular composition of sperm, alters the developmental trajectory of resultant embryos, and increase the incidence of obesity and metabolic disorders in offspring. Mechanistic candidates of paternal programming include changes to the sperm epigenome (eg DNA methylation, histone/protamine modifications, and sperm borne small non-coding RNAs), increased sperm DNA damage, aberrant sperm DNA chromatin structure, and components of seminal plasma. Understanding the molecular mechanisms underpinning paternal programming may lead to the development of interventions designed to reduce the disease burden in future generations, who were born to fathers exposed to these initiating factors. Given that these vices are predominantly self-inflicted, interventions aimed at mitigating their consequences are readily identified.

Add this information to all the other reasons to avoid these vices.

Alcohol And Cancer

Paper analyzing the role of alcohol consumption in cancer:

Abstract

BACKGROUND AND AIMS:

There is increasing research evidence about the causal role of alcohol in cancer, accompanied by unclear and conflicting messages in the media. This paper aimed to clarify the strength of the evidence for alcohol as a cause of cancer, and the meaning of cause in this context.

METHODS:

Recent epidemiological and biological research on alcohol and cancer was reviewed and summarized, drawing upon published meta-analyses identified from the Medline database and the archives of the International Agency for Research on Cancer. More recent epidemiological studies not included in these publications were also reviewed. A brief description of the nature of causal inference in epidemiology was used to frame discussion of the strength of the evidence that alcohol causes cancer, and contrast this with the case for a protective association of alcohol with cardiovascular disease.

RESULTS:

The usual epidemiological understanding of a cause is a factor that increases the incidence of a condition in the population. In the context of a body of epidemiological evidence of an association of alcohol consumption with a disease, the inference that it is a causal association requires alternative explanations of the observed finding to be judged unlikely. Even without complete knowledge of biological mechanisms, the epidemiological evidence can support the judgement that alcohol causes cancer of the oropharynx, larynx, oesophagus, liver, colon, rectum and breast. The measured associations exhibit gradients of effect that are biologically plausible, and there is some evidence of reversibility of risk in laryngeal, pharyngeal and liver cancers when consumption ceases. The limitations of cohort studies mean that the true effects may be somewhat weaker or stronger than estimated currently, but are unlikely to be qualitatively different. The same, or similar, epidemiological studies also commonly report protection from cardiovascular disease associated with drinking but a high level of scepticism regarding these findings is now warranted.

CONCLUSIONS:

There is strong evidence that alcohol causes cancer at seven sites in the body and probably others. Current estimates suggest that alcohol-attributable cancers at these sites make up 5.8% of all cancer deaths world-wide. Confirmation of specific biological mechanisms by which alcohol increases the incidence of each type of cancer is not required to infer that alcohol is a cause.

So, alcohol consumption likely promotes cancer but skepticism is warranted about it being protective against cardiovascular disease.

I myself only consume (small) amounts of alcohol infrequently at holidays. I see no reason to be drinking alcohol on a regular basis.