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“Although there is not total agreement on the nature and clinical significance of the effects of digitalis on the autonomic nervous system, the following points seem well established and generally accepted: I) the actions of digitalis on the autonomic nervous system are very important clinically and play a major role in determining the clinical pharmacodynamic effects of the drug; 2) with therapeutic concentrations of the drug, the predominant effect is activation of vagal tone; and 3) with toxic concentrations of the drug there may be activation of sympathetic tone.”   August M. Watanabe, 1985[1]

Abstract

In a central article published in the present edition of this journal was introduced a new hypothesis postulating stress (chronic sympathetic dominance) as the inductive factor for the increased lactate production found in cancer patients. In it has shown the important role of stress as the major risk factor for cancer, also discussing on how it develops lactate formation. [2]

In the present article is postulated that cardiac glycosides at low concentration doses fit perfectly well with the hypothesis of stress as the primary risk factor for cancer being these fundamental drugs for its prevention and therapeutic.

The article also discusses laboratory experimentation and clinical studies using cardiac glycosides. These have shown properties of induction of apoptosis and inhibition of proliferation of cancer cells. This apart of a large reduction in mortality of cancer, in patients taking these drugs at low concentration doses.

It also tells that some cardiac glycosides have shown sympathetic and glycolysis (glucose consumption and lactate) inhibitory effects.

Finally, this article explore the role of endogenous digitalis-like compounds in cancer and in other diseases.

Introduction

Our research on cancer started about 15 years ago. Follows an extract of the article “Digitalis: the Insulin for Cancer?, published at the News Bulletin of Infarct Combat Project from April 20, 2006, that is self-explanatory about my interest on the matter: [3]

“Digitalis: the Insulin for Cancer?

Coronary heart disease is the prime motivation of Infarct Combat Project (ICP). However, there are paramount cases in other medical conditions which ICP can’t neglect its participation and contribution. The present news is related with the use of an effective and inexpensive heart drug, for the treatment of cancer.

In a paper published in 2002 at Ars Cvrandi, a Brazilian medical journal, we have noticed an exceptional low mortality by cancer in cardiac patients treated with digitalis or other cardiac glycosides, when used in prevention of cardiac failure, unstable angina, acute myocardial infarction and sudden death. [4]

This case study involved 1150 patients with stable coronary heart disease. The follow-up period was 28 years. The cardiac glycosides employed were: Digitoxin, Digoxin, Acetyldigoxin, Betamethyldigoxin, Proscillaridin-A or Lanatoside-C at daily therapeutic oral doses - non-toxic, preferably lower.

It was shown in this study that the global mortality for the patients without previous myocardial infarction was 14.2% (0.5% per year) while the global mortality for the patients with previous myocardial infarction was 41.0% (1.4% per year). Surprisingly, the cancer mortality in these patients treated with digitalis or other cardiac glycosides was just 1.7% in total.

This curious information prompted us to verify the cancer mortality rate for patients in similar medical condition and age, presented in other studies. Also, we have made a search at Medline, finding out many studies showing digitalis as anticancer drug, with properties of inducing apoptosis (cell death) and inhibiting proliferation of cancer cells.

For the cancer mortality comparison the data was taken from a large study which had a follow-up of 5 years, involving 20.536 patients aged 40-80 years with coronary heart disease, other vascular diseases or diabetes.[5]

The bench-mark study found a cancer mortality of 3.3% (0.7% per year), in patients taking statin or placebo (inactive substance), while the study using digitalis or other cardiac glycosides, found a much lower mortality rate for cancer (0.06% per year).

Unfortunately, the astonishing finding of extremely low cancer mortality in the cardiac patients taking digitalis couldn’t be explored in the study signed by Quintiliano de Mesquita and Claudio Baptista. Cancer was not its main focus and a control group for this purpose was lacking.

Studies pointing to a reduction in mortality by cancer in patients taking digitalis are not new. In fact there are some writings stating that in the beginning of the past century the first study about this relationship was happened. Anyway, just in recent years the scientific confirmation came, suggesting digitalis as a potential anticancer agent”.

Before  presenting an update on the previous information published in 2006 at the News Bulletin from ICP, it is important to show the daily maintenance doses, for the cardiac glycosides used by Quintiliano de Mesquita and Claudio Baptista in their study. [4] It follows:

Daily Maintenance Doses [6]

•           Proscillaridin A:          0,75 – 1.50 mg

•           Acetyldigoxin:            0,50  mg 

•           Lanatoside C:             0,50 mg

•           Digitoxin:                   0,1 mg

•           Digoxin:                     0,125 – 0,25 mg

•           Betamethyldigoxin:     0,10 – 0,20 mg

Note: Digoxin, since its insertion, is still the cardiac glycoside most used in Brazil. Therefore, it represented a large proportion of the prescriptions from these authors to their patients. [6]

Cardiac Glycosides Tested for Cancer

Over the last decade it was augmented the range of cardiac glycosides used both as antitumor agents as in cancer prevention. Among the cardiac glycosides tested in studies for many cancer types, are included: digitoxin, digoxin, oleandrin, ouabain, lanatosid C, proscillaridin A, and bufalin.[7]

The Catalyst on the Research of Cardiac Glycosides for Cancer Therapy

Johan Haux and colleagues, in their seminal paper from 1999,[8] examined the effects of digitoxin and digoxin on some malignant cell lines with newly developed methods for estimating apoptosis. They found, for both of these cells lines, there was a dose response pattern and digitoxin in therapeutic concentration was more effective than digoxin in inhibiting these cell lines.

Haux, in a subsequent study,[9] pointed out that “Glycosides are common substances in herbal and plant extracts and the aglycone is usually poisonous. However, in lower concentrations, many of them exhibit antiproliferative effects on cancer cells. Interestingly, digitalis-like factors are also found in plasma from healthy individuals”.

Haux also told in his article [9]: “Until now, focus has been on the Na+/K+ATPase as the primary target for the effects of the digitalis compounds, also when it comes to explaining the anticancer effect. That is logical in view of the fact that halt of proliferation has been regarded as the main mechanism for explaining the inhibiting activities. However, now when we know that apoptosis induction is a major effect of digitalis on several types of tumor cells it seems fruitful to explore mechanisms other than just the Na+/K+ATPase inhibition”.

Digitoxin X Digoxin in the Treatment of Heart Failure

Up to the 1950s, digitoxin was the most commonly used glycoside in Germany; thereafter, Anglo-American prescription habits were quite closely followed and digoxin became more popular. However, France and Norway continued using digitoxin as their standard glycoside.

Digoxins are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate quite rapidly in cases of insufficient kidney function. The incidence of toxic side effects seems to be higher with digoxin than with digitoxin treatment.

In contrast, digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half life, is mainly eliminated in the metabolized state via urine and faeces, and does not accumulate under kidney dysfunction.

The daily oral maintenance dosages of digitoxin traditionally recommended are 0,05 mg, 0,07 mg or 0,1 mg in the objective of achieving a therapeutic serum concentration of digitoxin in the range of 10 to 30 ng/ml, depending on the assay used.  [10]

The daily oral maintenance dosages of digoxin traditionally recommended by guidelines, until 2010, were 0,125 mg, 0,250 mg and 0,375 mg in the objective of achieving a therapeutic serum digoxin concentration (SDC) in the range of 0.5 to 2.0 ng/ml. [12, 15]

Note: In vitro and ex vivo experiments have revealed that some cardiac glycosides (e.g, digitoxin) induce potent and selective anticancer effects, at concentrations commonly found in the plasma of patients treated with these drugs. [11]

Digoxin: Lowering the Dosage for Better Outcomes

Rathore et al, in a study published in 2003 [12], on a post hoc analysis of data from The Digitalis Investigation Trial (DIG) of1997 [13], dividing the man treated into three groups according to their serum digoxin concentration after one month of treatment: 0.5-0.8 ng/ml, 0.9-1.1 ng/ml and > 1.2 ng/ml, found that mortality in men in the lowest level group was 6.3% lower than that of men in the placebo group. In contrast, mortality in men in the intermediate and highest level groups was 2.6% and 11.8% higher respectively than that of the placebo group.

Adams et al, in a study published in 2005,[14] presenting another retrospective analysis of data from the DIG trial [13], have indicated a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrations > or =1.2 ng/ml seemed harmful.

The result of the studies from Rathore et al [12] and Adams et al [14] led to changes on the Heart Failure Guidelines issued by the Heart Failure Society of America in 2010. [15] Follows some extracts of the Session 7 of these guidelines related to the use of Digoxin recommendations from the chapter ‘Heart Failure in Patients with Reduced Ejection Fraction’:

1)         Recent data suggest that the target dose (and serum concentration) of digoxin therapy should be lower than traditionally assumed. Although higher doses may be necessary for maximal hemodynamic effects, beneficial neurohormonal and functional effects appear to be achieved at relatively low serum digoxin concentrations (SDC) typically associated with daily doses of 0.125 to 0.25 mg. A retrospective analysis of the relationship of SDC to outcomes in the DIG trial demonstrated a strong direct relationship between the risk of death and SDC, with concentrations ≥ 1.2 ng/mL being associated with harm, whereas concentrations ≤ 1.0 ng/mL were associated with favourable outcomes;

2)         The efficacy of digoxin in HF with reduced LVEF has traditionally been attributed to its relatively weak positive inotropic action arising from inhibition of sodium potassium ATPase and the resulting increase in cardiac myocyte intracellular calcium. However, digitalis has additional actions that may contribute significantly to its beneficial effects in patients with HF. Digoxin has important neuro-hormonal modulating effects that cannot be ascribed to its inotropic action, and it ameliorates autonomic dysfunction as shown by studies of heart rate variability, which indicate increased parasympathetic and baroreceptor sensitivity during therapy.

Note: Studies have shown an increased risk of breast and uterus cancer occurring in woman taking digoxin, with suggestion that these results were due to oestrogen like effects, because digoxin and digitoxin drugs are phyto-oestrogens, and that both breast and uterus cancers are often oestrogen sensitive. [16] The possible association with oestrogen brought some suspicion to the use of cardiac glycosides, particularly digoxin, in the treatment of cancers. This despite many studies indicating little evidence of an increased risk by digoxin in many cancer types like in lung, colon and prostate cancers. The digoxin exposure in studies, which found raised risk for breast and uterus cancers, was obtained through the national prescription database from Denmark, initiated in 1995 [15].  In view there was no knowledge in 1995 about better outcomes using digoxin at low concentration, it is extremely necessarily to make a retrospective analysis of data in these studies. This in order to verify the serum digoxin concentration, separating by groups of patients as done in the studies by Rathore et al [12] and Adams et al [14], in their analysis of The Digitalis Investigation Trial (DIG), from 1997. [13] We think that reviewing the results in this manner will lead to a closure on the case of cardiac glycosides, oestrogen and cancer.

Cardiac Glycosides and Sympatho-Inhibitory Effects

Studies have shown that the following cardiac glycosides drugs have a sympatho-inhibitory response:

•           Cedilanid* [17]

•           Digoxin [18, 19]

•           Digitoxin [20]

•           Ouabain [21]

*Cedilanid is the trade name. The active ingredient is Lanatoside C

Cardiac Glycosides in Reduction of Lactate Production

A recent paper has demonstrated that inhibiting the overproduction of catecholamine by digoxin, digitoxin and ouabain may induce a potent inhibition of glycolysis (glucose consumption and lactate) in cancer. [22] It confirm the results of old studies on this matter. [23]

Endogenous digitalis-like compounds (DLCs)

Endogenous DLCs like digoxin, ouabain/strophanthin, proscillaridin-A and marinobufagenin were isolated from human tissues and body fluids having similar molecular structure of cardiac glycosides extracted from plants and toad venom. [24,25]

Perturbation of the endogenous digitalis-like compounds system has been implied in many pathological conditions including cardiac arrhythmias, hypertension, heart failure, cancer and depressive disorders. [25, 26]

An example about this perturbation is the study which found that a majority (73.6%) of breast cancer patients (n = 84) expressed lower DLC plasma concentrations (<50 pmol/L) than a control group (150 ± 30 pmol/L), but about 10.8% of the patients revealed extremely high (>2000 pmol/L) DLC plasma concentrations. [27] Endogenous digitalis-like compounds may have similar action on neuro-hormonal levels.

The insufficient production of endogenous DLCs by the human body, to attend the demand in some medical conditions, like in cancer, hypothetically might be resolved through the use of cardiac glycosides at low concentration dosages as a supplement. We consider this view as an important direction in research of cancer whose investigators should pursue in the future. [28]

References

1.         Watanabe AM. Digitalis and the Autonomic Nervous System. JACC Vol. 5; No.5, 35 A - 42A: May 1985.

2.         Carlos ETB Monteiro, Stress as the Inductive Factor for Increased Lactate Production: The Evolutionary  Path to Carcinogenesis. Positive Health Online, Issue 241,  http://www.positivehealth.com/article/cancer/stress-inductive-factor-for-increased-lactate-production-evolutionary-path-to-carcinogenesis  October 2017.

3.         Carlos ETB Monteiro. Digitalis: the Insulin for Cancer? ICP,  http://www.infarctcombat.org/media/042006.html  April 2006 and
Monteiro, Carlos. Digitalis's Anticancer Effects (letter), Towsend Letter. #274 p.101, 2006

4.         Mesquita QHde. and Baptista CAS. Cardiotonic: Insuperable in preservation of myocardial stability, as preventive of acute coronary syndromes and responsible for a prolongued survival. Casuistic of 28 years (1972 -2000). Ars Cvrandi,, V 35 - N 3 - Original publication in Portuguese at http://www.infarctcombat.org/28years/digitalis.pdf  May 2002.

5.         The effects of cholesterol lowering with simvastatin on cause-specific mortality and on cancer incidence in 20,536 high-risk people: a randomized placebo-controlled trial, Heart Protection Study Collaborative Group. BMC Medicine, 3:6;  http://www.biomedcentral.com/content/pdf/1741-7015-3-6.pdf  2005.

6.         Mesquita QHde  et al. Effects of the Cardiotonic + Coronary Dilator in Chronic Stable Coronary-Myocardial Disease, with and without Prior Myocardial Infarction, in the Long Run. Ars Cvrandi,, V 35 - N 7 - Translation to English of the original publication in Portuguese at http://www.infarctcombat.org/CMD-CE.pdf  September 2002.

7.         Calderón-Montaño J et al.  Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides. BioMed Research International, Article ID 794930,  https://www.hindawi.com/journals/bmri/2014/794930/ 2014.

8.         Haux J., Lam M., Marthinsen A. B. L., Strickert T., Lundgren S. Digitoxin, in non toxic concentrations, induces apoptotic cell death in Jurkat T cells in vitro. Z Onkol / J Oncol; 1: 14–20:1999.

9.         Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Medical Hypotheses, 53(6); 543–548:2001.

10.       Belz GG et al. Treatment of congestive heart failure – current status of use of digitoxin. European Journal of Clinical Investigation, 31 (Suppl.2): 10-17: 2001.

11.       Lazaro ML et al. Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J. Nat Prod, 68:;1642-1645: 2005.

12.       Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM, Association of serum digoxin concentration and outcomes in patients with heart failure, JAMA, 289:871-878: 2003.

13.       The digitalis Investigating Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J. Med ,336;;525533: 1997.

14.       Adams KF Jr, Patterson JH, Gattis WA, O Connor CM, Lee CR, Schwartz TA, Gheorghiade M. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol. 2;46 (3):497-504: Aug 2005.

15.       Heart Failure Guidelines – 2010, from the Heart Failure Society of America. Published at Journal of Cardiac Failure;16:e1-e194: See section 7 at http://www.hfsa.org/heart-failure-guidelines-2  2010.

16.       Biggar R. Molecular pathways: Digoxin use and estrogen-sensitive cancers – Risks and possible therapeutic implications. Clin Cancer Res; 18(8) April 15, 2012.

17.       Ferguson DW et al. Sympathoinhibitory responses to digitalis glycosides in heart failure patients, Circulation, V80; N1, July 1980.

18.       Gheorghiade M. Digoxin, a neurohormonal modulator for heart failure? Circulation V84, N5; Nov 1991.

19.       Gheorghiade M, Adams KF, Colucci WS. Digoxin in the Management of Cardiovascular Disorders. Circulation, 109; 2959-2964:  http://circ.ahajournals.org/content/109/24/2959.long  2004

20.       Fardin NM et al. Digitoxin improves cardiovascular autonomic control in rats with heart failure. Can J. Pharmacol 94, 1-8; 2016.

21.       Gutman Y, Boonyaviroj P. Naunyn Schmiedebergs. Mechanism of inhibition of catecholamine release from adrenal medulla by diphenylhydantoin and by low concentration of ouabain (10 (-10) M). Arch Pharmacol,296(3);293-6: 1977.

22.       Calderón-Montaño J, Burgos-Morón E, Lopez-Lazaro M. The Cardiac Glycosides Digitoxin, Digoxin and Ouabain Induce a Potent Inhibition of Glycolysis in Lung Cancer Cells. WebmedCentral CANCER,;4(7);WMC004323:  https://www.webmedcentral.com/wmcpdf/Article_WMC004323.pdf  2013.

23.       Kypson J, Triner L, Nahas GG. The effects of cardiac glycosides and their interaction with catecholamines on glycolysis and glycogenolysis in skeletal muscle J Pharmacol Exp Ther,164(1); 22-30:1968.

24.       Schoner W. Endogenous cardiac glycosides, a new class of steroid hormones. Eur J Biochem, 268; 2440-2448: http://www.ejbiochem.org/cgi/content/full/269/10/2440  2002.

25.       Nesher M, Shpolansky U, Rosen H, Lichtstein D. 2007.The digitalis-like steroid hormones: New mechanisms of action and biological significance. Life Sci, 80(23);2093-107: 2007.

26.       Rose AM, Valdes RJ. Understanding the sodium potassium pump and its relevance to disease, Clin. Chem. 40/9; 1674-1685: 1994.

27.       Weidemann H.Na/K-ATPase, endogenous digitalis like compounds and cancer development - a hypothesis, . Front Biosci  Sep 1;10:2165-76: 2005.

28.       Carlos ETB Monteiro. Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. (Subtitle: Deficiency of endogenous digitalis-like compounds, the sodium potassium pump and cardiac glycosides), Available from Infarct Combat Project, http://www.infarctcombat.org/AcidityTheory.pdf  January 2008.