THE RELATIONSHIP BETWEEN CANNABINOIDS AND CANCER TREATMENT
INTRODUCTION
Cannabinoids are chemical compounds that can be classified in different categories.
The most part of them are known as been present in plants of the Cannabis’ spp: Cannabis Sativa and Cannabis Indica.These compunds are 21-carbon-containing terpenophenoli called Delta-9-tetrahydrocannabinol (THC), Cannabinol, Cannabidiol (CBD), Cannabichromene, Cannabigenol, Tetrahydrocannabivarine and
Delta-8-tetrahydrocannabinol.
These elements are called phytocannabinoids,as they come from plants. There are also endogenous cannabinoids,called endocannabinoids, which are produced by the human and also animal organism.They are: Anandamide (AEA), 2-Arachidonoilglycerol, 2-Arachidonil-glyceryl-ethere, Virodamin and N-Arachidonoildopamin (NADA).
The last category is made up by the synthetic cannabinoids which belong to different chemical groups: Aminoalkalyndoles, 1,5-Diarylpyrazoles, Quinolines and Arylsulphonamides.
Chemical structure of anandamide:
Chemical structure of tetrahydrocannabinol:
MOLECULAR ACTIVITY HUMAN CELLS OF CANNABINOIDS
Cannabinoids interact with two types of receptors: CB1 and CB2. CB1 receptors are present both in the CNS then PNS. In the CNS they are located in basal ganglia,hyppocampus,amigdala,cortex,cerebellum,hypotalamus,put
amen and nucleus caudatus.
The activation of CB1 receptors, which are seven-transmembrane-domain receptors,causes the inhibition of the Adenyl Cyclase, by the action of an inhibiting G-protein (Gi) and so the reduction of cAMP concentration in the cell. In the presinaptic neuron, this event causes the block of Calcium channel type N and Q, and the
activation of Potassium channel “inward rectifying”. As a conseguence there is a block of the release of many
neurotransmitters such as acetylcholine (hyppocampus), Noradrenaline (cortex,hyppocampus and sympatethic nerves) and Glutammate (cerebellum).CB1 activation also stimulates the ignition of the transduction pathway of MAP and ERK while reducing that of PKA.
The activation of CB1 receptors causes reduced locomotion and body temperature,catalepsy,memory impairment,sedation,euphoria,analgesia,anticonvulsant action and increase appetite.
In the PNS, CB1 are located in nerves,where their activation causes analgesia,reduction of cough and decreases intestinal transit. CB1 are also present in lungs,kidneys,liver,gut,stomach and genitalia.
CB2 receptors are located on the surface of T-lymphocytes and their activation induces immunomodulation.
They are also present in PNS where they induce analgesia and anti-inflammatory.
CANCER AND CANNABINOIDS
The relationship between cannabinoids and cancer is still nowadays controversal. It’s been demonstrate that cannabinoids have antitumoral effects on many types of neoplasms (lung, prostatic, breast, skin, glioma, pancreatic and lymphoma) and also they have palliative action on the cancer patients because they
reduce nausea and vomiting from chemiotherapics, stimulate appetite and reduce pain. Nevertheless the use of THC can cause lung and mouth damage,causing molecular abnormalities and histopatological alterations.
Concerning the antitumoral effect,cannabinoids are able to reduce cancer cell proliferation,angiogenesis, cell migration and metastasis plus inhibiting carcinogenesis and attenuating inflammatory process. The activation of the CB1 receptors, stimulates the ignition of the transduction pathway RAF-1-MEK-ERK, which has the effect of
blocking the cell cycle in phase Go/G1-S limiting the proliferation of the cell.
This happens through the activation of a Gi protein that blocks the adenylate cyclase, reducing the cellular levels of cAMP, and, consequently, the action of PKA. This allows the activation of transduction pathways (ERK, MAP-K, etc.) that promote the growth control and cell differentiation.
Stimulation of CB1 also causes the suppression of the activity of Ras, an oncogene, which, if expressed, increases the receptors for VEGF, a growth factor that induces angiogenesis.
cannabinoids also appear to be involved in the induction of apoptosis in tumor cells: it seems that the activation of the CB2 receptor induces an increase in intracellular ceramide, which, by increasing mitochondrial oxidative stress, due to the initiation of the apoptotic mechanism.Also receptor activation TRPV1 (vanillinic receptor) by anandamide (AEA) stimulates apoptosis. This is done through the increase of intracellular calcium, which activates the process of apoptosis.
MOLECULAR EVENTS IN CANCER CELLS:
As palliative care, the use of cannabinoids in cancer patients has several uses: combats nausea and vomiting induced by chemotherapy by means of interaction with CB1 receptors placed at the level of the myenteric plexus of stomach, duodenum and colon, as well as centrally where it acts directly on the vomiting center,
inhibiting. Furthermore, with the activation of CB1 receptors, counteracts the nociceptive chronic pain by blocking the transmission, either by acting on the CNS at the level of the thalamus, and medulla, cortex, either by interrupting the transmission device acting on the dorsal root ganglia and on the dorsal horn of the spinal cord. It is believed that the relief of pain is made possible thanks also to block the release of inflammatory mediators for activation of the CB2 receptors.
Finally stimulation of CB1 receptors at the central level corresponds to the increase in appetite, which counteracts the development of cachexia in the cancer patient.
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