Biology concepts – synergism, multidrug resistant cancers
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The Commiphora myrrha is the classic source for myrrh resin. It is a short tree that grows in low moisture and poor soil areas. Its branches are very thorny; some propose that the crown of thorns Jesus is said to have worn was made of myrrh twigs. |
The order goes along with representations of how he was born (as a king), how he lived (as a preacher), and how he died. But I think that sells myrrh short. True, it was used in consecrating and embalming dead bodies, but it is so much more. As with gold and frankincense, there is “myrrh” here than meets the eye.
Likefrankincense, myrrh is a resin from a tree that grows in the Middle East, in this case Yemen, Somalia, Eritrea, and Ethiopia. Frankincense and myrrh trees even come from the same family, the Bursceraceae. Being deciduous trees, both frankincense and myrrh are exceptions to the rule that coniferous trees are more likely to be resin producers.
Myrrh resin is an oleo-gum-resin, since it is has essential oils (oleo) and long polysaccharides (gums), as well as resins. It is more complex than frankincense, containing over 300 individual secondary metabolites and other compounds. Being a more complex substance, it might follow that myrrh would have more uses than frankincense, both in ancient times and now. And here is an instance in biology when the logical answer is the correct answer. In addition to being used as incense in rituals and perfumes, it had other mystical properties. It was so prized that it was often worth more than gold.
Greek soldiers always carried myrrh in their travel kits because it was a potent antibacterial and anti-inflammatory agent. Being soldiers, they were likely to be wounded, and those wounds would get infected and swell. If they died, it's good that they had myrrh, because it was also used as an embalming agent and to consecrate the dead bodies.
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In Greek mythology, Myrrha was a young lady who committed an awful no-no, and was chased across the desert by her father. The gods took pity on her and turned her into a tree so she wouldn’t have to run anymore. The myrrh resin that drips from the tree is said to be her tears. But I don’t get the part where she gives birth to Adonis while she is still a tree – family trees aren’t supposed to be literal. |
Myrrh smells good, but tastes horrible. In fact, the name myrrh originally came from the Aramaic word for bitter. To this day, the bitter taste of myrrh oil or powdered myrrh has limited it use in medicines. A recent study fiddled with making emulsions of myrrh in water in order to cover the taste, or adding fat-soluble compounds and using it as a suppository (there is usually good uptake of drugs from the south end of the gastrointestinal tract).
But the ancients still consumed myrrh despite the taste. It is said that someone gave Jesus myrrh dissolved in wine as a painkiller while he was on the cross. Others mixed it with red raspberry leaves to soothe a sore throat. Pliny the Elder wrote of using myrrh to kill bugs in wine and wine bottles before bottling the drink for transport and sale.
Though myrrh has been used for centuries, we have just now started to explain how myrrh functions in these capacities. For example, it is now known that compounds in myrrh called terpenes can interact with opioid receptors in the brain. This is how they act as painkillers.
Myrrh and frankincense components are also being tested in combination as antimicrobial agents. Oils of myrrh alone can kill or slow down some microorganisms; so can oils of frankincense. But adding them together has been shown to be a case of 1+1=3.
This is a demonstration of the concept of synergism. Let’s say that one antimicrobial drug can kill or stop X number of organisms when given at a certain dose. It is often the case that as you increase the dose, you will kill or stop more organisms – up to a point. Almost any drug becomes toxic when you ingest a lot of it. The lowest amount you can give to do the job is the miminal effective dose, and the most you can give is the maximum recommended safe dose.
To get a bigger bang for your buck, sometimes you can add a second drug to the regimen. Drug 1 inhibits or kills X number of organisms and drug 2 affects Y number of organisms. Often, giving drug 1 and 2 together will then inhibit or kill X+Y organisms. This is an additive effect. Drugs with additive effects often work on different targets; they are like eating a foot-long hotdog from both ends. The hotdog goes away twice as fast because the two mouths aren’t competing for the same part of the hotdog.
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The white dots are paper soaked in two different antibiotics. They are put on a plate of bacteria (the hazy diagonal lines). As the drugs diffuse out, they kill the bacteria (darker, clear areas, but their concentrations go down the farther they travel. But look between them, the area where they both are low concentrations is a bigger cleared area (between red lines). This is synergistic action. |
Synergism and additive effects are examples of pharmacodynamic effects; basically, how the drugs work on cells. We will later see how some drugs have pharmacokinetic effects on each other.
When a groupin South Africa tested two myrrh oils in combinations with three frankincense oils, they found that a combination of B. papyrifera and C. myrrha oils were synergistic in controlling both Cryptococcus neoformans, a fungus, and Pseudomonas aeruginosa, a gram negative bacterium.
The anti-inflammatory mechanisms of myrrh are just being worked out as well. Recent studies from South Korea indicate that myrrh stops the inflammatory process by inhibiting the production of molecules that promote inflammation. Their 2011 studyindicates that myrrh turns off the enzymes that produce nitric oxide, prostaglandins, and some inflammatory cytokines (messengers that have many effects) when inflammation was stimulated by LPS, a cell wall component of many bacteria called lipopolysaccarhide, also called endotoxin. LPS is responsible for things like septic shock and necrotizing enterocolitis.
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Rheumatoid arthritis (arthus = joint, and itis = inflammation of) is mediated by an autoimmune process that brings much inflammation. Myrrh has been used for hundreds of years as an anti- inflammatory drug, but we are just now figuring out why it works. |
But even they did not suspect all the wonders of myrrh. It is with cancer that one myrrh component is turning out to be a gift. There are several species of myrrh trees, and a couple, C. mukul and C. molmol, contain a compound called guggulsterone (I love saying that name out loud – go ahead, it’s fun). Guggulsterone is not necessarily toxic to cancer cells by itself, but it may solve a big problem that currently affects many cancer treatments.
We talked a while ago about how bacteria have pumps to kick antibiotics out of their cell, and thereby prevent their action. Cancer cells also have a pump to do this to many cancer chemotherapeutic drugs. The most common of these drug pumps is a membrane channel protein called P-glycoprotein (P-gp). This protein is present in some normal types of cells, working to pump out toxic compounds, like in liver cells and skin cells. This means that cancer drugs on these types of cancers have a hard time staying in the cells.
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P-gp pumps cancer drugs back out of cells with the help of changing ATP to ADP. This can lead to drug resistant cancers. We are looking for inhibitors that might block the action of P-gp by taking away its ATP or by competing with the drug for the pump, so less drug is pumped out. |
Enter guggulsterone (let’s call it GGS for short) – new research shows that this compound from myrrh can reverse MDR in several types of cancer. The mechanism is just now being uncovered; GGS can act as a competitive inhibitor of P-gp, meaning that it is pumped out just like the cancer drugs. But the more time P-gp spends pumping out GGS, the less time it is pumping out cancer drug, so it becomes more effective. It does not appear that GGS stops production of P-gp or other actors in this play, it just keeps them busy – but it does it without being toxic. This is a pharmacokinetic effect, one drug (GSS) has an effect on how another drug (cancer drug) is acted on by the cells, in this case by keep the drug in the cancer cell much longer.
In the cases of pancreatic cancer and gall bladder cancer, very new studies show that GGS in combination with the cancer drug gemcitabine, works much better than the drug alone. The combination causes higher levels of apoptosis in these cancers, perhaps through the action of keeping more drug in the cancer cells, but GGS may have other cytotoxic effects as well.
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Osteoporosis leads to less dense bones, which can alter posture and lead to bone breaks. It looks like the guggulsterone in myrrh can prevent bone resorption after menopause. It may even increase density and be a treatment for bone breaks. |
Next week – the biology of New Years’ resolutions!
For more information or classroom activities, see:
Myrrh –
Additive and synergistic effects in pharmacology –
Multidrug resistance in cancer –
http://mayoresearch.mayo.edu/mayo/research/chang_lab/