Are ‘Exercise In a Pill’ Drugs Like Cardarine Dangerous?

Hello and welcome to my blog!

This is part of the controversial compounds series of blogs. This week is all about cardarine/GW501516 and  GW0742

Cardarine also called GW501516 and a stronger version called GW0742 are a class of supplement called ‘exercise in a pill’ or ‘endurance boosters’. They are not stimulants, SARMS or steroids, but they are banned in sport. These compounds escaped into the fitness industry a few years ago, so they are not new or secret and are  used regularly by fitness enthusiasts, athletes and bodybuilders.

There are many ‘unlicensed pharmaceuticals’ and supplements which are used by the public for a variety of reasons other than for performance and the users pretty much  swear by these alternative drugs

But are they safe?

Before diving into detail on these interesting and potentially useful drugs, which are peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands, let me explain a bit of the  biochemistry and history behind these rather complicated sounding drugs.

What do proliferator-activated receptor-β/δ (PPARβ/δ) ligands like cardarine actually do?

These compounds are not performance or party drugs, they are research chemicals which show great potential for treating metabolic syndrome, cardiovascular disease, inflammation, diabetes and obesity, even in mice fed on a high fat diet. These compounds can  increase serum HDL cholesterol (good cholesterol), increase fatty acid breakdown  in skeletal muscle, improve insulin resistance and inhibit inflammation.

 

 

So there is no wonder these (PPARβ/δ) ligands are of interest to both scientists and the public.

For a while research and development of these compounds was hampered due to contradictory and controversial  findings on their potential safety. However,  new research has now shed light on some of the studies and questioned the methods, models, doses and cell types.

What is a peroxisome?

A peroxisome is a type of organelle known as a microbody, found in cells and plays a role in energy expenditure, particularly fat metabolism and other functions including making hydrogen peroxide and plasmalogen.  An enzyme called catalase uses the hydrogen peroxide (which is poisonous to cells) to perform detoxification reactions on nasty compounds which enter the cells. As we age our levels of catalase go down and this is in part why hair goes grey/white. Plasmalogen is the most abundant phospholipid in myelin and low levels of  plasmalogens causes profound abnormalities in the myelination (insulation) of nerve cells and conditions like MS.

Interestingly, human peroxisomes don’t have an enzyme called uric acid oxidase which breaks down uric acid which causes gout, which is why animals and plants don’t suffer this painful problem.

One of the main function of the peroxisome is breaking down very long chain fatty acids, converting them to medium chain fatty acids (MCT/MCFA), which are  shuttled to mitochondria (cell battery) where they are eventually broken down to carbon dioxide and water. For more on the biochemistry of fat and fat metabolism see ‘The biochemistry of Fat Myths’ 

As you can see the peroxisome is a pretty cool organelle and if they work properly  have many important health benefits

 

What is a peroxisome proliferator-activated receptor?

 

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins (like a biological lock) that function as transcription factors regulating the expression of genes, ie switching genes on and off when a ligand (biological key) binds to them. PPARs, the receptors were discovered in Xenopus frogs (giant clawed frogs with special eggs), as receptors that induce the proliferation (growth)  of peroxisomes in cells.

We now know that these PPARs have many other functions relating to metabolism of glucose and fat, as well as cell growth and differentiation. It is noteworthy that compounds which promote cell growth theoretically could encourage cancer cells to grow, but some compounds when tested in a lab, turn out to have the opposite or unexpected results.

To make things more confusing, the peroxisome proliferator-activated receptor (PPAR) family has three different variants: PPAR α (alpha), PPAR β/δ (beta/delta)  and PPAR γ (gamma)  which are found in different cell types.

  • α (alpha) – expressed in liver, kidney, heart, muscle, adipose tissue, and others
  • β/δ (beta/delta) – expressed in many tissues but markedly in brain, adipose tissue, and skin
  • γ (gamma) has 3  variants from alternative splicing of the gene.
  • γ1 – expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
  • γ2 – expressed mainly in adipose tissue (30 amino acids longer than γ1)
  • γ3 – expressed in macrophages, large intestine, white adipose tissue.

For the receptor to do something  ie alter metabolism, burn fat etc in need a ligand, like cardarine to bind to it.

So far I have covered what a peroxisome is,  that PPAR is a receptor that is found in many cell types and when it is activated this receptor influences metabolism and cell growth by altering the expression of genes. A ligand, which is a compound that binds to a receptor and basically makes something happen. In this blog the ligand  is carderine/GW501516 or  GW0742 so the ‘exercise in a pill’ drug is the ligand for the PPAR.

Do exercise in a pill drugs cause cancer or was the research inaccurate?

While some reports suggest that PPARβ/δ ligands (drugs to bind to the PPAR)  promote the growth of cancer cell lines, there are many many observations inconsistent with this hypothesis. Some of the contradictory findings could be due in part to differences in the ligand examined, very large doses, the presence or absence of serum in cell cultures, differences in cell lines, or differences in the method used to quantify cell growth.

Studies showed colon cancer cell lines fail to exhibit an increase in cell growth by PPARβ/δ in either the presence or absence of serum. Additionally, more recently it was shown that two different PPARβ/δ ligands inhibit cell growth of human liver and colon cancer cell lines, independent of culture medium serum and in another study inhibited  the growth of both MCF7 (breast cancer) and UACC903 (melanoma) cell lines and provide further evidence that PPARβ/δ ligands do not cause cell division in human cancer cell lines. A study in 2018 using cardarine /GW501516 showed it nasopharyngeal carcinoma in C666-1 cells by promoting cancer cell death.

PPAR/δ ligands like carderine are now showing promise as molecular tools for chemoprevention of certain types of cancers. An increasingly  large body of evidence is now showing  that ligand activation of PPARβ/δ can prevent tumor promoting inflammation, could reverse sustained cancer cell growth and increase sensitivity to cancer suppressing drugs.

Given the relatively small number of studies that have examined the effect of ligand activation of PPARβ/δ on breast, prostate and lung cancer cell growth, further studies are needed before firm conclusions can be drawn.  Although a  recent study in 2017 using GW501516 /Cardarine showed that it suppressed migration and invasion of breast cancer cells by down-regulating (lowering levels) of Thrombospondin-1  (TSP-1). TSP-1 is a glycoprotein that when unchecked in the cells has a carcinogenic effect that promotes metastasis and progression of breast cancer.

Other benefits

On a different note, the anti-inflammatory activity of PPARβ/δ  ligands has been shown in a number of different studies and cells types; including immune cells, colon epithelium, macrophages, heart cells, keratinocytes, myoblasts, endothelial cells, nerve tissue and liver cells. This of course is very beneficial, as systemic inflammation is at the heart of lots of chronic diseases and conditions.

PPAR/δ ligands like carderine have shown to improve  serum lipid profile, HDL levels (good cholesterol) and insulin sensitivity in several animal models, so they are a promising treatment for metabolic syndrome,  type 2 diabetes and genetic obesity, the original reason they were of interest to scientist.

In addition, PPARβ/δ ligands prevent weight gain in obesity prone mice, and in humans too (from anecdotal evidence). All of the factors above contribute to cancer and other health related issues, meaning that the scales have tipped in favor of PPARβ/δ ligands, with new evidence suggesting that this class of ‘exercise in a pill’ drug may turn out to be safe and beneficial after all.

Like any compound it is best to do your own research rather than just ‘sucking and seeing’.

Thank you for reading next controversial biochemical topic will be on the tanning drug Melanotan 2

 

 

 

 

References 

van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, Kuipers F. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1. J Lipid Res. 2005

Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A. 2003;100:15924–1592

Wallace JM, Schwarz M, Coward P, Houze J, Sawyer JK, Kelley KL, Chai A, Rudel LL. Effects of peroxisome proliferator-activated receptor {alpha}/{delta} agonists on HDL-cholesterol in vervet monkeys. J Lipid Res. 2005

Leibowitz MD, Fievet C, Hennuyer N, Peinado-Onsurbe J, Duez H, Bergera J, Cullinan CA, Sparrow CP, Baffic J, Berger GD, Santini C, Marquis RW, Tolman RL, Smith RG, Moller DE, Auwerx J. Activation of PPARdelta alters lipid metabolism in db/db mice. FEBS Lett. 200

Peters J. M., Gonzalez F. J., Muller R. (2015a). Establishing the role of PPARbeta/delta in carcinogenesis. Trends Endocrinol. Metab. 26 595–607.

Peters J. M., Yao P. L., Gonzalez F. J. (2015b). Targeting peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) for cancer chemoprevention. Curr. Pharmacol. Rep. 1 121–128.

Hollingshead HE, Killins RL, Girroir EE, Billin AN, Willson TM, Sharma AK, Amin S, Gonzalez FJ, Peters JM. Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands do not potentiate growth of human cancer cell lines. Carcinogenesis. 200

Shimada T, Kojima K, Yoshiura K, Hiraishi H, Terano A. Characteristics of the peroxisome proliferator activated receptor gamma (PPARgamma) ligand induced apoptosis in colon cancer cells. Gut. 2002;50:658–664

Girroir EE, Hollingshead HE, Billin AN, et al. Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines. Toxicology. 2008;243(1-2):236-243

Aung C. S., Faddy H. M., Lister E. J., Monteith G. R., Roberts-Thomson S. J. (2006). Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation. Biochem. Biophys. Res. Commun. 340 656–660

Peters, Jeffrey M., Jennifer E. Foreman, and Frank J. Gonzalez. “Dissecting the Role of Peroxisome Proliferator-Activated Receptor-Β/δ (PPARβ/δ) in Colon, Breast, and Lung Carcinogenesis.” Cancer metastasis reviews 30.3-4 (2011).

Front Pharmacol. 2018; 9: 648.

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