Breast cancer is the most common cancer in women worldwide. Despite advances in early detection, it remains the second leading cause of cancer death in American women, mostly attributed to drug-resistant refractory tumors.
A study published this year showed that out of 612 participants, 42% reported use of cannabis for relief of symptoms and 49% believed cannabis could be used to treat cancer itself. In recent years, as the legalization of cannabis expands, cannabis and the endocannabinoid system have increasingly become topics of interest for the treatment of various conditions.
The dysregulation of our endocannabinoid system has been associated with several diseases, including cancers. Evidence reveals that the endocannabinoid system is altered in breast cancer. An increasing number of studies also highlight the role that cannabinoids have in cancer spreading. Specifically these report on invasion, angiogenesis, migration, and metastasis.
The Endocannabinoid System (ECS)
Our ECS is the largest neurotransmitter system in the body composed of endocannabinoids, cannabinoid receptors, and metabolizing enzymes. Endocannabinoids are arguably one of the most widespread and versatile signaling molecules known to man; two key endocannabinoids that have been identified are Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG). The endocannabinoids activate different receptors throughout the body and brain called CB1 and CB2 receptors. CB1 receptors are found in high levels in the brain and central nervous system; whereas CB2 receptors are found in numerous immune cells and the peripheral nervous system.
Modulation and activation of the cannabinoid receptors by these endocannabinoids can have various effects within the body. It is likely that endocannabinoids impact several cancer-related signaling pathways. For example, AEA has been shown to inhibit breast cancer cell growth and migration in multiple mouse model studies. It is known that in breast cancer, CB2 receptors are over-expressed and CB1 is present in lower quantities
Findings of the endocannabinoid system have inspired further studies to take place with exogenous or phytocannabinoids, that mimic the actions of endogenous cannabinoids and their interactions with cannabinoid receptors.
Most existing cancer therapies are not developed to specifically target metastatic progression, despite tumor metastasis accounting for 90% of cancer-related deaths. Breast cancer, in particular, has been noted as typically incurable once clinically apparent metastases develop, therefore there is a need for non-toxic therapeutic interventions to target this progression.
There has been compelling evidence of the anti-tumoral activity of cannabinoids in preclinical models of breast cancer, both witnessed in cell culture systems and clinically relevant animal models. In recent years, the two most abundant cannabinoids found in Cannabis sativa, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), have been more closely studied for their anti-tumor activity against a variety of aggressive cancers, with each compound having its own unique mechanism of action. It has been proposed in research that targeting both cannabinoid anti-tumor pathways simultaneously, by combining THC and CBD, may lead to enhanced anti-tumor activity.
A study published in the British Journal of Pharmacology in 2014, demonstrated that moderate doses of CBD were effective at inhibiting metastatic progression in female mice, leading to prolonged survival in multiple preclinical models of breast cancer. This study also discovered that while moderate doses of CBD could have this inhibiting effect, higher doses were required to inhibit tumor growth.
Although the strength of experimental data is different for each case, evidence obtained so far suggests that cannabinoid therapies may be useful for these breast cancer subtypes:
Hormone-sensitive (ER+ / PR+)
Cell Death and Cell Growth
Apoptosis is a form of programmed cell death. Apoptosis in cancer aids specifically in cancer cell death. This activity is well documented across several cancer models while undergoing cannabinoid therapy. Published research from 2011 shows that CBD induced not only apoptosis but also autophagy-induced death in breast cancer cells. CBD was shown to preferentially target breast cancer cells by inducing estrogen receptor (ER) stress and enhancing reactive oxygen species (ROS).
Another study published in 2006 explains that CBD exerts its effects on these cells through a combination of mechanisms that include either direct or indirect activation of CB2 and TRPV1 receptors and induction of oxidative stress, which may all contribute to induce apoptosis.
Antiproliferation is the suppression of cell growth. Data gathered in 2015 for the American Association for Cancer Research studied the effects of CBD, THC, CBN, and CBG on proliferation of breast cancer cells. Among the tested, CBD was the most potent inhibitor of human breast cancer cell aggressiveness.
Considering other cannabinoids
When it comes to cancer models, the anticancer activity of CBDA was investigated on acute lymphocytic leukemia, promyelocytic leukemia cells, and human prostate carcinoma androgen receptor positive cells. CBDA was found to be less active than CBD for all of these, until tested towards MDA-MB-231 cells, a highly aggressive triple negative breast cancer. CBDA was found to inhibit breast cancer cell migration. The data in the report showed that CBDA offers “potential therapeutic modality in the abrogation of cancer cell migration, including aggressive breast cancers”.
Initial findings in literature and research show CBG potential as a therapeutic agent in helping slow the proliferation of breast cancer cells, therefore possibly lessening tumor severity. CBG may also be useful as an anti-emetic or anti-inflammatory to complement traditional cancer treatments.
Terpenes and Flavonoids
Terpenes are compounds found in all known life forms, including fruits, trees, herbs, and a range of other plant species that are responsible for determining their distinct scents. There is a complex diversity and varying concentration of terpenes in cannabis plants. Yet, quality research is available in regard to terpene-specific benefits, although not all research is available in living models as of yet. B-Caryophyllene, limonene, pinene, linalool, bisabolol, humulene, terpineol, and nerolidol are among those studied for apoptosis effects. As well, limonene, pinene, linalool, edesmols, eucalyptol, terpineol, and camphene are associated with reduced tumor growth.
Flavonoids account for nearly 10 percent of compounds known in cannabis and may represent up to 2.5 percent of cannabis’ leaf and flower dry weight. They are the largest class of polyphenols. Kaempferol, apigenin, cannflavin B, silymarin, and luteolin are among those researched for tumor-reduction abilities. Kaempferol is also associated with reduced metastasis. Orientin, vitexin, and isovitexin have been studied to induce apoptosis.
Additional benefits of cannabinoids in breast cancer
A feature of cannabinoid anti-tumor action in breast cancer, as well as other cancer types, is that there is no toxicity observed in non-tumor cells. With this, and other observations, cannabinoids have adopted the reputation as having safe profiles. In fact, they have proven safe in thousands of individuals among many clinical trials in cancer patients.
Preclinical and clinical evidence suggests the efficacy of CBD and THC in targeting cancer-associated pain, anxiety and depression, sleep issues, nausea and vomiting, and oral mucositis that are associated with cancer and traditional treatments. These same studies also suggest that cannabinoids may enhance the efficacy of traditional treatments such as chemotherapy and radiation therapy, as well as protect against neural and organ damage.
The most realistic approach in clinical trials has been introducing this therapy in combination with standard treatment. The evidence has shown the combination does not have negative effects and that anti-tumor effects were actually improved.
Hormone-receptor positive breast cancer
Around 70-80% of breast cancers are hormone receptor-positive (HR+)
There is preclinical evidence that the molecular pathways between the cannabinoid receptors within our body and estrogens overlap, which may impact the pathogenesis of common diseases including HR+ breast cancer. In one study, researchers concluded that the endocannabinoid, AEA, blocks human breast cancer cell proliferation, however evidence for anti-tumor cannabinoid action in HR+ breast cancer is less clear. There are many possible interactions between HR+ breast cancer and exogenous and endogenous cannabinoids but currently there are no clinical trials evaluating the effect of cannabinoids on treatment outcomes and/or prognosis.
The interactions between HR+ breast cancer and exogenous and endogenous cannabinoids, specifically, are reported as nearly impossible to predict. The use of cannabinoid therapy in palliative medicine is well established, but researchers indicated that clinical trials are needed to determine the safety of cannabinoid therapy in various other breast cancer settings. Until we have this further evidence there should be an emphasis on close monitoring when using cannabinoid therapy in an HR+ breast cancer setting.
Although the majority of reports published to date show that cannabinoids induce anti-tumor responses, not only for breast cancers but many other types, there are a reduced number of articles that have reported pro-tumor actions in response to cannabinoid therapy. In two published cases, both observed pro-tumor effects of cannabinoids were either undetectable or very low levels of cannabinoid receptors were present; therefore the interaction between cannabinoids and cannabinoid receptors was not fully observed or understood. As well, it has been hypothesized that pro-tumoral versus anti-tumoral effects may be explained by the biphasic effects of cannabinoids, where too little or too much may result in opposite effects.
Therefore, it is important when starting out with cannabinoid therapy to be transparent with your doctor so you may be closely monitored and to ease into your therapy so you may understand how the cannabinoids interact with your body and specific diagnosis.
A call for more research
Among the published articles that are available, there is a common call to additional research to further provide evidence for the use of cannabinoid therapy for specific conditions. Results obtained are optimistic thus far, however breast cancer is diverse and we have a long way to go before we fully understand the role of cannabinoids in each breast cancer subtype.
This is one of the many reasons why Realm of Caring has partnered with Johns Hopkins University School of Medicine for our Observational Research Registry. This allows individuals to self-report their condition, products being used (or not being used), how much they are taking, and when they are taking it in their natural environment. This observational data helps to further pave the way for clinical research, legitimize plant-based therapies, and destigmatize the cannabis plant.
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