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.
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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.
Like frankincense, 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.
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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.
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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 group in 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 study
indicates 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.
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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.
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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.
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Next week – the biology of New Years’ exercise 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/
