Cancer-specific Cytotoxicity of Cannabinoids
By: Dennis Hill
First let's look at what keeps cancer cells alive, then we will come back and
examine how the cannabinoids CBD (cannabidiol) and THC (tetrahydrocannabinol)
unravels cancer's aliveness.
In every cell there is a family of interconvertible sphingolipids that
specifically manage the life and death of that cell. This profile of factors is
called the "Sphingolipid Rheostat." If ceramide (a signaling metabolite of
sphingosine-1- phosphate) is high, then cell death (apoptosis) is imminent. If
ceramide is low, the cell will be strong in its vitality.
Very simply, when THC connects to the CB1 or CB2 cannabinoid receptor site on
the cancer cell, it causes an increase in ceramide synthesis which drives cell
death. A normal healthy cell does not produce ceramide in the presence of THC,
thus is not affected by the cannabinoid.
The cancer cell dies, not because of cytotoxic chemicals, but because of a tiny
little shift in the mitochondria. Within most cells there is a cell nucleus,
numerous mitochondria (hundreds to thousands), and various other organelles in
the cytoplasm. the purpose of the mitochondria is to produce energy (ATP) for
cell use. As ceramide starts to accumulate, turning up the Sphingolipid
Rheostat, it increases the mitochondrial membrane pore permeability to
cytochrome c, a critical protein in energy synthesis. Cytochrome c is pushed out
of the mitochondria, killing the source of energy for the cell.
Ceramide also causes genotoxic stress in the cancer cell nucleus generating a
protein called p53, whose job it is to disrupt calcium metabolism in the
mitochondria. If this weren't enough, ceramide disrupts the cellular lysosome,
the cell's digestive system that provides nutrients for all cell functions.
Ceramide, and other sphingolipids, actively inhibit pro-survival pathways in the
cell leaving no possibility at all of cancer cell survival.
The key to this process is the accumulation of ceramide in the system. This
means taking therapeutic amounts of cannabinoid extract, steadily, over a period
of time, keeping metabolic pressure on this cancer cell death pathway.
How did this pathway come to be? Why is it that the body can take a simple plant
enzyme and use it for healing in many different physiological systems? This
endocannabinoid system exists in all animal life, just waiting for it's matched
exocannabinoid activator.
This is interesting. Our own endocannabinoid system covers all cells and nerves;
it is the messenger of information flowing between our immune system andthe
central nervous system (CNS). It is responsible for neuroprotection, and micro-
manages the immune system. This is the primary control system that maintains
homeostasis; our well being.
Just out of curiosity, how does the work get done at the cellular level, and
where does the body make the endocannabinoids? Here we see that endocannabinoids
have their origin in nerve cells right at the synapse. When the body is
compromised through illness or injury it calls insistently to the
endocannabinoid system and directs the immune system to bring healing. If these
homeostatic systems are weakened, it should be no surprise that exocannabinoids
perform the same function. It helps the body in the most natural way possible.
To see how this works we visualize the cannabinoid as a three dimensional
molecule, where one part of the molecule is configured to fit the nerve or
immune cell receptor site just like a key in a lock. There are at least two
types of cannabinoid receptor sites, CB1 (CNS) and CB2 (immune). In general CB1
activates the CNS messaging system, and CB2 activates the immune system, but
it's much more complex than this. Both THC and anandamide activate both receptor
sites. Other cannabinoids activate one or the other receptor sites. Among the
strains of Cannabis, C. sativa tends toward the CB1 receptor, and C. indica
tends toward CB2. So sativa is more neuroactive, and indica is more immunoactive.
Another factor here is that sativa is dominated by THC cannabinoids, and indica
is predominately CBD (cannabidiol).
It is known that THC and CBD are biomimetic to anandamide, that is, the body can
use both interchangeably. Thus, when stress, injury, or illness demand more from
endogenous anandamide than can be produced by the body, its mimetic
exocannabinoids are activated. If the stress is transitory, then the treatment
can be transitory. If the demand is sustained, such as in cancer, then treatment
needs to provide sustained pressure of the modulating agent on the homeostatic
systems.
Typically CBD gravitates to the densely packed CB2 receptors in the spleen, home
to the body's immune system. From there, immune cells seek out and destroy
cancer cells. Interestingly, it has been shown that THC and CBD cannabinoids
have the ability to kill cancer cells directly without going through immune
intermediaries. THC and CBD hijack the lipoxygenase pathway to directly inhibit
tumor growth. As a side note, it has been discovered that CBD inhibits
anandamide reuptake. Here we see that cannabidiol helps the body preserve its
own natural endocannabinoid by inhibiting the enzyme that breaks down anandamide.
This brief survey touches lightly on a few essential concepts. Mostly I would
like to leave you with an appreciation that nature has designed the perfect
medicine that fits exactly with our own immune system of receptors and signaling
metabolites to provide rapid and complete immune response for systemic integrity
and metabolic homeostasis.
~Dennis Hill
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NIH Public Access: A house divided: ceramide, sphingosine, and
sphingosine-1-phosphate in programmed cell death Tarek A. Taha, Thomas D.
Mullen, and Lina M. Obeid Division of General Internal Medicine, Ralph H.
Johnson Veterans Administration Hospital, Charleston, South Carolina 29401; and
Department of Medicine, Medical University of South Carolina, Charleston, South
Carolina 29425 Corresponding author: Lina M. Obeid, M.D., Department of
Medicine, Medical University of South Carolina, 114 Doughty St., P.O.Box 250779,
Charleston, South Carolina 29425. E-mail: obeidl@musc.edu