Author : Dr.Elmo Resende, Ph.D
| Director of R&D - Piauhy Labs
Cancer is a term used to describe diseases that have in common the fact that they are the result of an uncontrollable growth of cells, which can invade neighboring tissues. There are over 100 different diseases that can have specific nominations, such as cervical cancer, prostate cancer, lung cancer and leukemia.
This disease is also known as neoplasm. The medical science that studies cancer is called Oncology and the oncologist is the professional who treats the disease. Untreated cancers cause serious illness and death.
Cancer starts when cells in some organ or tissue in the body start to grow out of control. This growth is different from healthy cell growth. Instead of dying, cancer cells keep growing and forming new abnormal cells. Cancer cells can also invade other tissues, which healthy cells cannot. Out-of-control growth and invasion of other tissues is what turns a healthy cell into a cancer cell.
The endocannabinoid system is formed by cannabinoid receptors, endocannabinoids, metabolizing enzymes and the membrane transporter. With the elucidation of cannabinoid receptors, scientists have increased curiosity about the existence of endogenous ligands and have been trying to understand how to intervene in the modulation of the system, whether using synthetic cannabinoids or phytocannabinoids (extracted from Cannabis sativa), such as ∆9-Tetrahydrocannabinol (∆9-THC), or simply THC, Cannabidiol (CBD), Cannabigerol (CBG) and Cannabinol (CBN).
The endocannabinoid system is a set of receptors and enzymes that act as signalers between cells and body processes.
Through several studies and researches, it was possible to identify three key elements that compose the endocannabinoid system: the endocannabinoids, the cannabinoid receptors and the enzymes. Endocannabinoids are synthesized in the body and act as signaling molecules that bind to receptors in the endocannabinoid system. "Endo" means "inside" and "cannabinoid" refers to any molecule that activates these receptors. The two main endocannabinoids in the human body are anandamide and 2-AG.
Several different mechanisms have been related to the anti-tumorigenic actions of endocannabinoids and include cytotoxic or cytostatic effects, induction of apoptosis and anti-metastatic effects, such as inhibition of neo-angiogenesis and migration of tumor cells. These effects are either dependent on the CB1 and CB2 receptors and TRPV1, or are independent of the receptor based on the cannabinoid or endocannabinoid and on the tumor tissue or cell.
In the central nervous system, endocannabinoids act as neuromodulators or retrograde messengers that inhibit the release of various neurotransmitters; in peripheral and neural tissues, they modulate the effects of proteins and nuclear factors involved in cell proliferation, differentiation and apoptosis, as paracrine or autocrine mediators. These data suggest that endocannabinoids may play an important role in controlling cell fate.
Various plant-derived cannabinoids (e.g. THC and CBD), synthetic cannabinoids (e.g. WIN-55, 212-2 and HU-210) and endogenous cannabinoids (e.g. anandamide and 2-arachidonoylglycerol) are now known for exerting antiproliferative actions on a broad spectrum of cultured tumor cells. More importantly, administration of cannabinoids to mice retards the growth of several tumor xenografts, including lung carcinomas, gliomas, thyroid epitheliomas, skin carcinomas, and lymphomas. The need for CB1 and/or CB2 receptors for this antitumor effect has been demonstrated by various biochemical and pharmacological approaches, in particular by the determination of cannabinoid receptor expression and the use of selective cannabinoid receptor agonists and antagonists. In one study, it was suggested that endocannabinoids exert their apoptotic effect by binding to the vanilloid receptor type 1 (VR1), a non-selective cationic channel directed by capsaicin, the active component of hot chili pepper. However, the precise role of this receptor in cannabinoid signaling is not fully understood.
Cannabinoids affect several cellular pathways by binding to and activating their specific G protein-coupled cannabinoid receptors. They inhibit the adenylyl cyclase-cyclic AMP protein (cAMP) kinase A pathway and modulate the activity of Ca2+ and K+ channels, which they inhibit the release of neurotransmitters. Cannabinoids also modulate several signaling pathways that are more directly involved in controlling cell fate.
The anticancer mechanism of action of cannabinoids depends, at least in large part, on the ability of these agents to stimulate autophagy-mediated apoptotic cell death. Thus, THC binds to cannabinoid receptors, which leads to stimulation of de novo sphingolipid synthesis and subsequent activation of an ER stress-related signaling pathway that involves the upregulation of transcriptional coactivating nuclear protein 1 (Nupr1, also called of p8) and its effector, the tribbles pseudo-kinase homologue 3 (TRIB3). Stimulation of this pathway, in turn, promotes autophagy through TRIB3-mediated inhibition of the AKT/mTORC1 axis. Autophagy is mainly considered a cytoprotective mechanism, although its activation can also lead to cell death.
CBD exerts a significant anticancer effect and specifically the inhibition of invasiveness and metastasis, which is observed in different animal models of cancer, acting independently of cannabinoid receptors. This effect of CBD depends, at least partially, on the down-regulation of ID-1 (inhibitor of the DNA-binding transcription factor-1).
CBD interacts with receptors other than CB1 and CB2, such as the TRPV1 receptor, the orphan G protein-coupled receptor (GPR55), or the peroxisome proliferator-activated receptors (PPARs). These three receptors, TRPV1, GPR55 and PPARs, have been suggested to be classified as CB receptors, but their exact role in endocannabinoid signaling is still under discussion. CBD has anxiolytic properties and attenuates the psychoactive effects of THC.
CBD is not intoxicating, so its potential use as a therapeutic agent is more attractive than some other cannabinoids that have psychoactive effects, such as THC. To date, there are many studies around the anticancer potential of CBD. Treatment with CBD has shown a multitude of beneficial anticancer effects on lung, breast, colon, prostate, melanoma, leukemia, cervical, cerebral, neuroblastoma and multiple myeloma cancer cells.
Many studies show the heterogeneity of cancer, in that each cancer subtype, and even each individual tumor, exhibits a number of molecular characteristics that determine its behavior and, in particular, its responsiveness to different anticancer drugs. In agreement with this line of reasoning, a recent study investigated the molecular characteristics that are associated with the resistance of a collection of human glioma cell lines and primary anti-tumor cultures of cannabinoids. The study showed that although the apoptotic effect of THC on glioma cells depended on stimulation of CB receptors and activation of the p8-mediated autophagy pathway, differences in sensitivity to THC-induced cell death correlated with enhanced expression of a set of genes in THC-resistant glioma cells. Studies show that different cannabinoids affect cell growth and survival in different types of cancer. However, the underlying mechanisms involved can be heterogeneous and specific to different cells. Cannabinoids can target the tumor directly, thus affecting cell signaling and pathways that eventually induce cell growth arrest, cell death, and also inhibit cancer cell migration. They can also indirectly mediate their effects through the tumor microenvironment, the immune response and/or the prevention of vascularization.
Current cancer-fighting strategies are based on the use of combined anticancer therapies, as this approach allows for simultaneous targeting of the fight against tumor growth at different levels. According to this line of reasoning, the combined administration of cannabinoids with other anticancer agents demonstrates a synergistic action to inhibit tumor growth. Thus, treatment with THC and TMZ exerts a strong anticancer action on xenografts generated with glioma cells. Importantly, this effect also occurs in TMZ-resistant tumors.
Studies carried out with adults undergoing chemotherapy in outpatient cancer centers in some states of the United States of America have shown that the common reasons why these patients use cannabis and cannabinoids include nausea and vomiting (21%), anxiety (20%), improved quality of life/general well-being (17%), decreased pain (15%), improved appetite or weight gain (12%), depression (9 %) and the cancer treatment itself (4%).
Pain is a common symptom that more than half of cancer patients experience, and cannabis has been shown to be effective in reducing pain. Cannabis has also been identified as being able to interact with opioid receptors and presents itself as an alternative to opioids. Furthermore, while loss of appetite and anorexia are common symptoms of concern among cancer patients, cannabis is known to increase appetite and observational data show this benefit among cancer patients. To some extent, there is evidence to support cannabis' potential for additional symptoms that affect cancer patients, such as gastrointestinal discomfort, peripheral neuropathy, as well as depression and anxiety.
In breast cancer cells, THC, at a concentration of 14 µM, inhibited overall cell growth and proliferation, exposure to THC showed that it inhibits estradiol-induced cell proliferation by inhibiting α-estrogen receptor activation. In glioma cell lines, treatment with THC produced a dose-dependent inhibition of cell viability and proliferation. In glioma cells, treatment with THC at 3 µM was able to inhibit cell growth. In a leukemia model, THC had an IC50 of 13 µM and CBD had an IC50 of 8 µM. When THC and CBD were combined in a 1:1 ratio, the IC50 was lowered to 4 µM. The combinations of THC and CBD also slightly sensitized the leukemic cells to the anticancer agents, vincristine and cytarabine. The beneficial effects of combination therapy with cannabinoids and chemotherapeutic agents depended on the sequence of administration; increased cell death was observed when cannabinoids were administered after chemotherapy.
As a result of the intended research processes, Piauhy Labs wants to create patents and originate intellectual property, with the ultimate goal of producing innovative medicines, medicines that improve the quality of life of patients suffering from various diseases, including cancer.
Elmo Resende, Ph.D
Director of R&D
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Autism is a psychiatric problem that is usually identified in childhood, between 1 year and a half and 3 years, although the initial signs sometimes appear in the first months of life. The disorder affects the child’s communication and the ability to learn and adapt.