Cancer and the ECS

Cannabinoids and Cancer Cells

A vast amount of evidence confirms that cannabinoids can reduce tumor growth in animal models of cancer. This is done by regulating key cell signaling pathways involved in the control of cancer cell proliferation and survival. Cannabinoids also inhibit angiogenesis and cell proliferation in different types of tumors seen in laboratory animals.

Cannabinoids have been shown to continuously inhibit cancer cells via different pathways.

• Cancer is triggered by certain factors such as smoking or drinking. Cancer is the uncontrolled proliferation of cells and invasion of those cells into surrounding tissue.
• Cannabinoids are anti-proliferative and activate apoptosis and autophagia.
• As cancer cells divide or proliferate, an increase number of CB1 and CB2 receptors form in the tissue.
• Apoptosis is programmed cell death. Apoptosis is the body’s ability to mark a cell for destruction.
• Autophagia is the body’s ability to consume its own cell that’s been marked for destruction
• Cannabinoids facilitate the inhibition of tumor cell proliferation via apoptosis of tumor cells and impairing tumor angiogenesis.
• Different cannabinoids from different sources, regulate and modulate different signaling pathways.
• The use of a single cannabinoid maybe beneficial, however there is a synergistic affect seen when cannabinoids are combined with other cannabinoids, endocannabinoids, flavonoids, or phyto-cannabinoids.

Bone Cancer

• The ECS plays a significant role in bone turn over and bone mass development. Chondrosarcoma and osteosarcoma are the most common type of primary bone cancers. Bone metastasis is when a primary cancer like breast or prostate spreads from its primary organ and infiltrates a secondary organ.
  • Bone metastasis is a common complication of cancer and the most frequent type of pain related to cancer.
  • Administration  of cannabinoids JWH-015 and AM1241 attenuated tumor-evoked tactile allodynia and thermal hyperalgesia by reducing NR2B-dependent activity. CB2 agonist, JWH-015 reduced breast cancer induced bone pain, bone loss, and breast cancer cell proliferation via cytokine/chemokine suppression in murine mammary cell line implanted into the femur intramedullary space.
• The cannabinoid receptor agonist, WIN 55, 212-2, attenuates tumor-evoked hyperalgesia through peripheral mechanisms

Breast Cancer

• Breast cancer has a few categories that divide its classifications. According to The World Health Organization, the classifications are based on histopathology and include, but are not limited to: Invasive Carcinomas, Tubular Carcinomas, Papillary Carcinomas, Neuroendocrine tumors (atypical, oat cell, nueroendocrine), Inflammatory Carcinoma, Mesenchymal Tumors, Hemangiomas, Lipomas, Carcinoma In Situ and Invasive (both in male)With so many different cancers in males and females, its hard to say what all the causes can be stemming from. There are also genetic markers like Human Epidermal Growth Factor receptor 2 (HER2) and Cancer Antigen (CA 15-3) that help us identify what treatments can help certain patients and whether these treatments are affective or not. Cannabinoids play a major role in modulating the growth of hormone sensitive breast cancer cells.
  • CBD has been shown to be the key mediator between apoptosis and autophagia in breast cancer cells
    • A study in 2011 published in Molecular Cancer Therapeutics titled, Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy, has a very clear perspective on a very crucial role in cancer therapeutics. From the implications of the title, we can deduce the outcome. Cannabidiol (CBD) induces (starts the process) Programmed Cell Deacth (aka Apoptosis) in Breast Cancer cells by coordinating (communicating) the Cross-talk (problem to be solved) between Apoptosis (programmed cell death) and Autophagy (auto- meaning self, -phagy meaning to eat; eating and self destruction of the cell). The title now broken down tells us what to expect from the study. The study of Cannabinoids such as CBD revealed the ability to induce concentration-dependent cell death in breast cancer lines.

• • “In summary, we showed that CBD, a plant-derived cannabinoid, preferentially kills breast cancer cells by inducing ER stress, inhibiting mTOR signaling, enhancing ROS generation, and mediating a complex balance between autophagy and mitochondria-mediated apoptosis in MDA-MB-231 breast cancer cells.”

Colon Cancer

• Cannabinoid receptor agonists induce phosphatases and phosphatase-dependent apoptosis in cancer cell lines; however, the role of the CB receptor in mediating this response is ligand-dependent.

Glioma

• Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer.
  • Gliomas exhibit high resistance to conventional chemotherapies.
  • “CBD treatment induces apoptosis in glioma cells in vitroand tumor regression in vivo through activation of caspases and reactive oxygen species via receptor-independent manner Furthermore, studies revealed that CBD induced TRPV2-dependent Ca²⁺ influx which triggers the drug uptake and synergizes with cytotoxic agents to induce apoptosis of glioma cells”
  • combined treatment of Δ⁹-THC and temozolomide (TMZ) exert a strong antitumoral action in glioma xenografts by inducing autophagy
  • Administration of CBD- and THC-loaded poly-ε-caprolactone microparticles reduced tumor growth, cell proliferation and increased apoptosis in mice bearing glioma xenografts.
• Cannabinoids inhibit N-Type calcium channels in Neuroblastoma-glioma cells

Head and Neck Cancer

• A population-based case control study suggests that moderate marijuana use is associated with a reduced level of HNSCC (Head Neck Squamous Cell Carcinoma)

Leukemia

Acute Lymphoblastic Leukemia (ALL) is a cancer of white blood cells. Traditional line of care is chemo and radiation. However, cannabis brings new hope for a safer alternative.

• There is an abundance of research exhibiting the cytotoxic effects of cannabinoids on leukemic cell lines in the form of in vitro and in vivo studies
• One study showed a dose response curve was achieved. Three factors, namely frequency of dosing, amount given (therapeutic dosing) and the potency of the cannabis strains, were critical in determining response and disease control. In the figure,
• It can be observed that introducing strains that were less potent, dosing at intervals >8 h and suboptimal therapeutic dosing consistently showed increases in the leukemic blast cell count.
• Targeting cannabinoid receptors to treat leukemia: Role of cross-talk between extrinsic and intrinsic pathways in Δ⁹-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells
• Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic diseaseCulture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis.
•  The CB₂ cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway
• Cannabidiol-Induced Apoptosis in Human Leukemia Cells: A Novel Role of Cannabidiol in the Regulation of p22^phox and Nox4 Expression
• • cannabidiol exposure led to an increase in reactive oxygen species (ROS).
  • An increase in the expression of the NAD(P)H oxidases Nox4 and p22^phox was observed.
  • Cannabidiol exposure led to a decrease in the levels of p-p38 mitogen-activated protein kinase.
  • “The results from this study reveal that cannabidiol, acting through CB2 and regulation of Nox4 and p22^phoxexpression, may be a novel and highly selective treatment for leukemia.”

Lung Cancer

• Lung cancer has one of the highest mortality rates among cancer-suffering patients.
  • Cannabinoids could halt tumor development without side effects via specific targeting of CB1/CB2 receptor.
  • Studies suggest the involvement of COX-2 and PPAR-γ in CBD’s proapoptotic and tumor-regressive action in A549, H460 cells and primary cells from a patient with lung cancer.
  • CBD caused up-regulation of COX-2 and PPAR-γ in tumor tissue and tumor regression in A549-xenografted nude mice.
  • JWH-133 induced anti-proliferative potential in A549 cell line via DNA fragmentation.
  • Blocking FAAH increases the levels of AEA, which in turn inhibits EGFR signaling pathway, leading to cell cycle arrest and apoptosis.
• Self-administration of CBD oil showed marked improvement in a patient with histologically proven adenocarcinoma of the lung

Lymphoma

• Mantle Cell Lymphoma (MCL) is reported to exhibit over expression of CB1/ CB2 receptors.

• Cannabinoid receptor ligand treatment caused a decrease in viability of MCL cells
• Treatment with the CB1/CB2 agonist Win-55,212-2 caused a decrease in long-term growth of MCL cells in culture
• Win-55,212-2 contribute their ability to suppress tumor growth via activation of apoptosis

Oral Cancer

• Oral cancers include cancers of the lips, mouth and throat. These cancers have a higher incidence in patients who smoke, chew tobacco or drink alcohol.

• Δ⁹-THC was shown to induce apoptosis in a malignant form of oral cancer known as Oral Squamous Cell Carcinoma (OSCC)

Pancreatic Cancer

• Normal and cancerous pancreatic tissue was shown to express CB1 and CB2 receptors.
  • Cannabinoid administration leads to apoptosis of pancreatic tumor cells via CB2 receptors and ceramide-dependent up-regulation.
  • An additional study showed “pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.”

Prostate Cancer

• Prostate cancer was shown to have a higher expression of CB1/CB2 receptors in tissue.
  • One study showed “treatment of prostate cancer cells with cannabinoid CB1/CB2 agonist WIN-55,212-2 results in a dose and time dependent decrease in cell viability ,and increased apoptosis along with decrease in androgen receptor protein expression, PSA expression, and secreted PSA, suggesting that cannabinoids should be considered as agents for the management of prostate cancer.”
  • Anandamide, 2-AG, THC, cannabidiol, and its stable analogue noladin have exerted apoptotic, anti-proliferative, and anti-invasive effects in different prostate cancer cells both in vitro and in vivo.

Skin Cancer

Melanoma is the leading cause of skin cancer deaths worldwide.

• Normal mammalian epidermis contains CB 1 and CB2 receptors.
  • Studies confirm the “Activation of CB1/CB2 receptors induced the apoptotic death of tumorigenic epidermal cells, without affecting the nontrans formed epidermal cells.”

Thyroid Carcinoma

• 2-methyl-2′-F-anandamide (Met-F-AEA) induced apoptosis in thyroid carcinoma cells via activation of p53 and p21 mediated pathway.IL-12 gene transfer was also observed