Cannabis is a well-regarded therapy for a number of diseases and Lymphoma is a type of cancer that not only displays the trademark side. If your dog suffers from lymphoma, I'm sure you've heard the news that CBD can . From my research into cancer and CBD, I've learned that the most common . in capsule form, which is a good option for dogs that might not like the CBD oil. Most cancers are identifiable through their names like testicular cancer or skin cancer, but lymphoma's target isn't in the title. Lymphoma attacks.
vs cbd oil lymphoma cancer
In lung cancer, CBD inhibits invasion of A cells both in vitro and in vivo that was accompanied by up-regulation of tissue inhibitor of matrix metalloproteinase-1 TIMP-1 and decreased expression of plasminogen activator inhibitor-1 PAI-1 [ - ]. In skin cancer, treatment of WIN, or JWH caused impairment of tumor vascularization and decreased expression of proangiogenic factors such as VEGF, placental growth factor, and angiopoietin-2 [ 85 ].
In glioma, [ ], one study reveals that CBD also inhibits angiogenesis by modulating MMP-2 pathway and Id-1 gene expression in glioblastoma cells [ - ]. CBD inhibits cell proliferation and invasion of 4T1 cells mammary metastatic cell line and reduces primary tumor volume as well as lung metastasis in 4T1-xenografted orthotopic model of nude mice [ - ].
This anti-metastatic effect was mediated by downregulation of Id-1 a basic helix-loop-helix transcription factor inhibitor , ERK and also by inhibiting the ROS pathway.
Furthermore, CBD reduced the number of metastatic foci in 4T1- tail vein injected syngenic model. Cancer stem cells CSC are part of the tumor cell population.
Though they might be very less in number, they have the ability to self renew and replicate to produce enormous cancer cell types. CSCs have been shown to be drug resistant with higher invasive and metastatic potential [ ]. Studies show that cannabinoid receptors are involved in differentiation of neural progenitors from ectoderm and hematopoietic progenitors from mesoderm. CB1 and CB2 receptor activation modulate proliferation and differentiation of daughter progenitors.
It involved partial regulation by cannabinoid receptors leading to oxidative stress, necrosis coupled with apoptosis. These open further investigation on the function of cannabinoids and the link between stem cell and tumor progression. Increased ROS production has been associated with triggering of apoptosis [ ]. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers [ - ].
The combination of cannabinoids and gemcitabine, a nucleoside analogue used in cancer chemotherapy, synergistically inhibit pancreatic adenocarcinoma cell growth by a ROS-mediated autophagy induction without affecting normal fibroblasts [ ]. Cannabidiol CBD -induced endoplasmic reticulum stress mediated cell death of MDA-MB breast cancer cells, with the coexistence of autophagy and apoptosis [ 63 ]. In primary lymphocytes, treatment with CBD induced caspase 8 induced apoptosis which was mediated by oxidative stress.
Similar result has been reported in glioma cells where CBD causes oxidative stress and higher enzymatic activities of glutathione reductase and glutathione peroxidase. KM induced mitochondrial depolarization, cleaved caspase 3, significant cytoskeletal contractions, and redistribution of the Golgi-endoplasmic reticulum structures in U87MG human GBM cells [ ].
Cancer is a type of inflammatory disease, where immune cells infiltrate into the tumor site and secrete factors which enhance the prospects of proliferation, angiogenesis and metastasis [ ]. Hence, it is important to identify anti-cancer agents that target the immune related cancer environment. In glioma, WIN, caused accumulation of ceramide which is essential for cell death and it also had anti-inflammatory effects [ ]. Cannabinoids exert a direct anti-proliferative effect on tumors of different origin.
They have been shown to be anti-migratory and anti-invasive and inhibit MMPs which in turn degrade the extra-cellular matrix ECM , thus affecting metastasis of cancer to the distant organs. Also, cannabinoids modulate other major processes in our body like energy metabolism, inflammation, etc.
These data are derived not only from cell culture systems but also from more complex and clinically relevant animal models. Before cannabinoids could be used in clinical trials, there is need to explore more knowledge on several issues such as anti-tumorigenic and anti-metastatic mechanisms as well as which type of cancer patient populations would be more responsive for cannabinoid based therapies.
Data presented in this review suggest that cannabinoids derived from different sources regulate differently signaling pathways, modulate different tumor cell types and host physiological system.
It is important to understand which of the cannabinoid receptors are expressed and activated in different tumors as each receptor follows a different signaling mechanism.
Furthermore, endocannabinoids- AEA and 2-AG are broken down into secondary metabolites like prostaglandin PGE 2 and epoxyeicosatetraenoic acid EE which enhance tumor growth and metastasis in diverse cancer types.
Understanding the exact signaling by which cannabinoids function will eventually lead to targeted clinical approach. Also, the difference in cellular response to cannabinoids in different cancer types might be due to the effect of the tumor environment which involves inflammatory cells, fibroblasts, endothelial cells, macrophages, etc.
Thus, there is a need for an integrative understanding of the role of cannabinoids with respect to the tumor and its microenvironment. The diversity of affecting multiple signaling pathways might pave way for developing cannabinoids that selectively obstruct a particular pathway, thus opening avenues for specific targeted treatments. Moreover, cannabinoids are more specific to cancer cells than normal cells.
The administration of single cannabinoids might produce limited relief compared to the administration of crude extract of plant containing multiple cannabinoids, terpenes and flavanoids.
Thus, combination of cannabinoids with other chemotherapeutic drugs might provide a potent clinical outcome, reduce toxicity, increase specificity and overcome drug resistance complications. Additional findings in in vitro and in vivo models are needed to support studies at preclinical setting. The authors disclose no competing interests. National Center for Biotechnology Information , U. Journal List Oncotarget v. Published online Jul Author information Article notes Copyright and License information Disclaimer.
Received May 19; Accepted Jul This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article has been cited by other articles in PMC. Abstract The pharmacological importance of cannabinoids has been in study for several years. Cannabinoid receptors, cannabinoid agonists, cancer, signaling. Cannabinoid and its receptor Cannabinoids can be classified into three groups based on their source of production; endogenous cannabinoids endocannabinoids , phytocannabinoids and synthetic cannabinoids Fig. Table I Cannabinoid's structure and its role in different physiological processes.
Docosatetraenyl ethanolamide CB1 agonist neuromodulatory and immunomodulatory [ ]. Oleamide CB1 agonist neuromodulatory and immunomodulatory [ ]. Open in a separate window. Cannabinoids and their classification This figure illustrates how cannabinoids are divided into three main categories according to their availability in nature. Endogenous cannabinoids Endogenous cannabinoids which are produced in our body include lipid molecules containing long-chain polyunsaturated fatty acids, amides, esters and ethers that bind to CB1 or CB2 receptors.
Phytocannabinoids Phytocannabinoids are only known to occur naturally in significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. Synthetic cannabinoids Synthetic cannabinoids have been extensively used as a pharmacological agent, both in vitro and in vivo , to obtain more detailed insight of cannabinoid action, in order to evaluate their potential clinical use.
Cannabinoid mediated signaling in cancer cells Cannabinoids activate CB1 or CB2 receptor which in turn modulates diverse signaling targets.
Table II Role of cannabinoid in different cancers and its associated signaling. Cannabinoids Anti-cancer effect and its mechanism of action Anandamide 1 Breast cancer: Suppression of nerve growth factor Trk receptors and prolactin receptors Prostate cancer: Attenuates mechanical hyperalgesia HU 1 Prostate cancer: MMPs pathway 3 Skin cancer: Mitogenic at low doses 4 Glioma: Role of cannabinoids in regulation of cancer growth One of the important aspects of an effective anti-tumor drug is its ability to inhibit proliferation of cancer cells.
Cannabinoids and breast cancer Breast cancer is one of the most common human malignancies and the second leading cause of cancer-related deaths in women, and its incidence in the developing world is on the rise [ 40 - 41 ]. Cannabinoids and prostate cancer Prostate cancer is the most common malignancy among men of all races and is one of the leading causes of cancer death in this population. Cannabinoids and lung cancer Lung cancer has one of the highest mortality rates among cancer-suffering patients.
Cannabinoids and skin cancer Melanoma is the mainly cause of skin cancer—related deaths worldwide. Cannabinoids and pancreatic cancer Pancreatic cancer is one of the most aggressive and devastating human malignancies. Cannabinoids and bone cancer Chondrosarcoma and osteosarcoma are the most frequent primary bone cancers [ 89 ]. Cannabinoids and glioma Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer, exhibit high resistance to conventional chemotherapies.
Cannabinoids and oral cancer Oral cancer is mainly occurs in the mouth including lips, tongue and throat. Cannabinoids and head and neck cancer Marijuana smoking increases the incidence of head and neck cancer in young people but its constituent, cannabinoids have anti-tumor properties. Cannabinoids and thyroid carcinoma Thyroid carcinoma is the most aggressive form which occurs in thyroid gland. Role of cannabinoids in pro-metastatic mechanisms like angiogenesis, migration and invasion Migration and invasion are characteristic features of cancer cells.
Role of cannabinoids in stemness and cancer Cancer stem cells CSC are part of the tumor cell population. Role of cannabinoids in immune environment and cancer Cancer is a type of inflammatory disease, where immune cells infiltrate into the tumor site and secrete factors which enhance the prospects of proliferation, angiogenesis and metastasis [ ].
Footnotes The authors disclose no competing interests. Medical use of cannabis. Harvey Lecture, February 19, Bull N Y Acad Med. Cannabis use for chronic non-cancer pain: Cannabinoids for cancer treatment: Functionally selective cannabinoid receptor signalling: Structure of a cannabinoid receptor and functional expression of the cloned cDNA.
Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Distribution of cannabinoid receptors in the central and peripheral nervous system. Molecular characterization of a peripheral receptor for cannabinoids. Felder CC, Glass M.
Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol. The endocannabinoid system as an emerging target of pharmacotherapy. Towards the use of cannabinoids as antitumour agents. Cannabimimetic fatty acid derivatives in cancer and inflammation.
Prostaglandins Other Lipid Mediat. Neurobiology Cannabinoids act backwards. Ruminska A, Dobrzyn A. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.
Biochemistry of the endogenous ligands of cannabinoid receptors. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Occurrence and metabolism of anandamide and related acyl-ethanolamides in ovaries of the sea urchin Paracentrotus lividus. Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor.
Effects of two endogenous fatty acid ethanolamides on mouse vasa deferentia. Chemical characterization of a family of brain lipids that induce sleep. Structural determinants of the partial agonist-inverse agonist properties of 6'-azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabinoid receptors. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion.
International Union of Pharmacology. Classification of cannabinoid receptors. Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Inhibition of glioma growth in vivo by selective activation of the CB 2 cannabinoid receptor. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor CB2: J Pharmacol Exp Ther. Binding of the non-classical cannabinoid CP 55,, and the diarylpyrazole AM to rodent brain cannabinoid receptors.
SRA, a potent and selective antagonist of the brain cannabinoid receptor. SR , the first potent and selective antagonist of the CB2 cannabinoid receptor. Hanahan D, Weinberg RA. The hallmarks of cancer. Ocana A, Pandiella A. Identifying breast cancer druggable oncogenic alterations: Comparative study on the use of analytical software to identify the different stages of breast cancer using discrete temperature data.
Baselga J, Swain SM. Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Deltatetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cells.
The cannabinoid CB1 receptor antagonist rimonabant SR inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation.
Anandamide inhibits adhesion and migration of breast cancer cells. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells. A role for L-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells.
Homeostatic chemokine receptors and organ-specific metastasis. Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Delta 9 -tetrahydrocannabinol inhibits 17beta-estradiol-induced proliferation and fails to activate androgen and estrogen receptors in MCF7 human breast cancer cells.
JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Anandamide inhibits Cdk2 and activates Chk1 leading to cell cycle arrest in human breast cancer cells. Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB 1 Arch Toxicol.
Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. A high cannabinoid CB 1 receptor immunoreactivity is associated with disease severity and outcome in prostate cancer.
Increased expressions of cannabinoid receptor-1 and transient receptor potential vanilloid-1 in human prostate carcinoma. J Cancer Res Clin Oncol. Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism.
Involvement in Raf-1 stimulation and NGF induction. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. Guindon J, Hohmann AG. The endocannabinoid system and cancer: The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation.
Involvement of CB1 cannabinoid receptor and Raf Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.
Anti-proliferative and anti-angiogenic effects of CB2R agonist JWH in non-small lung cancer cells A and human umbilical vein endothelial cells: Folia Biol Praha ; 58 2: Cannabinoid receptors as novel targets for the treatment of melanoma. Cannabinoids in pancreatic cancer: Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism.
Cartilage tumours and bone development: Management of bone metastases. A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: J Pain Symptom Manage. Differential effects of repeated low dose treatment with the cannabinoid agonist WIN 55, in experimental models of bone cancer pain and neuropathic pain.
A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss. The cannabinoid receptor agonist, WIN 55, , attenuates tumor-evoked hyperalgesia through peripheral mechanisms. Acute and chronic administration of the cannabinoid receptor agonist CP 55, attenuates tumor-evoked hyperalgesia. Reduction of bone cancer pain by activation of spinal cannabinoid receptor 1 and its expression in the superficial dorsal horn of the spinal cord in a murine model of bone cancer pain.
Spinal and peripheral analgesic effects of the CB2 cannabinoid receptor agonist AM in two models of bone cancer-induced pain. Intrathecal administration of the cannabinoid 2 receptor agonist JWH can attenuate cancer pain and decrease mRNA expression of the 2B subunit of N-methyl-D-aspartic acid. Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists.
J Bone Miner Res. Inhibition of tumor angiogenesis by cannabinoids. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression.
Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. A combined preclinical therapy of cannabinoids and temozolomide against glioma.
Amphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosis. Stimulation of ALK by the growth factor midkine renders glioma cells resistant to autophagy-mediated cell death. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme. Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma.
The role of cannabinoid receptors and the endocannabinoid system in mantle cell lymphoma and other non-Hodgkin lymphomas. Enhancing the in vitro cytotoxic activity of Delta9-tetrahydrocannabinol in leukemic cells through a combinatorial approach.
Potentiation of cannabinoid-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism. Concomitant consumption of marijuana, alcohol and tobacco in oral squamous cell carcinoma development and progression: A population-based case-control study of marijuana use and head and neck squamous cell carcinoma. Cancer Prev Res Phila ; 2 8: Cannabinoid 2 receptor induction by IL and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma.
A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis. Cell migration in tumors. Curr Opin Cell Biol.
Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis. The cytoskeleton and cancer. AEA has the highest affinity in both cases, whereas 2-AG has the highest efficacy in both cases [ 14 ]. Physiological or pathological stimuli induce synthesis and release of endocannabinoids, which can subsequently activate cannabinoid receptors. Cannabinoids are currently used in cancer patients to palliate wasting, emesis and pain that often accompany cancer.
A significant advancement in cannabinoid use in cancer treatment came from the discovery of a potential utility of these compounds for targeting and killing cancer cells.
In Munson et al. The interest in anticarcinogenic properties of cannabinoids was even renewed after the discovery of the eCB system and the cloning of the specific cannabinoid receptors. Since then, several cannabinoids have been shown to exert anti-proliferative and pro-apoptotic effects in various cancer types lung, glioma, thyroid, lymphoma, skin, pancreas, uterus, breast, prostate and colorectal carcinoma both in vitro and in vivo [ 18 — 26 ]. Moreover, other antitumourigenic mechanisms of cannabinoids are currently emerging, showing their ability to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization [ 27 ].
Interestingly CBD has no psychotropic activity and, although it has very low affinity for both CB 1 and CB 2 receptors, it has been recently reported to act with unexpectedly high potency in vitro as antagonist of CB 1 receptors in the mouse vas deferens [ 28 ] and brain [ 29 ] tissues.
Besides its beneficial effects in the treatment of pain and spasticity and other CNS pathologies, several reports demonstrated that CBD possesses antiproliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion. This review will focus on the most recent evidence regarding the efficacy of CBD in the modulation of tumourigenesis in several types of cancer. The data available so far are summarized in Table 1 and are discussed in detail in the following paragraphs.
In Ligresti et al. Later on, McAllister's group [ 31 ] demonstrated that, besides proliferation, CBD also interfered with two other crucial steps of breast cancer cell progression, invasion and metastasization. Interestingly, CBD regulated the expression of key genes involved in the control of cell proliferation and invasion through the downregulation of Id-1 expression, an inhibitor of basic helix-loop-helix transcription factors, whose overexpression in breast cancer cells is responsible for proliferation, migration and invasion.
Therefore, the ability of CBD to decrease significantly Id-1 expression in breast cancer cells was associated with its efficacy in reducing tumour aggressiveness. Four years later , the same group [ 32 ] demonstrated that the observed effect of CBD on Id-1 expression was mediated by the upregulation of the extracellular signal-regulated kinase phosphorylation pERK.
Moreover, these authors demonstrated that CBD was effective in reducing the primary tumour mass and the size and number of metastatic foci in vivo. Finally , the excellent paper of Shrivastava et al. These authors showed that CBD induced a concentration-dependent cell death of both oestrogen receptor-positive and oestrogen receptor-negative breast cancer cells with a mechanism independent of CB 1 , CB 2 and TRPV1 receptor activation. Interestingly, the effective concentrations of CBD in tumour cells have little effect on non tumourigenic, mammary cells.
Examining further the cellular mechanism involved in CBD-induced cell death, they found that CBD reduced mitochondrial membrane potential, triggered the translocation of the Beclin2 interacting protein Bid to the mitochondria and the release of cytochrome C to the cytosol and, ultimately, the activation of the intrinsic apoptotic pathway.
Finally, the relationship between CBD-induced apoptosis and autophagic cell death was explored by blocking each form of cell death with specific inhibitors. CBD treatment induced the cleavage of Beclin1 and the subsequent translocation of the cleavage product to the mitochondria where it may induce apoptosis through the enhancement of cytochrome C release [ 34 , 35 ].
As a whole this work highlights the presence of a complex balance between autophagy and mitochondria-mediated apoptosis in CBD-induced breast cancer cell death and strengthens the idea that CBD can be considered as an alternative agent for breast cancer therapy. Figure 3 shows a schematic representation of the signalling pathways associated with the effect of CBD in breast cancer cell proliferation and invasion.
Schematic representation of the signalling pathways associated with CBD effects on breast cancer. CBD also possesses anti-tumoural properties in gliomas, tumours of glial origin characterized by a high morphological and genetic heterogeneity and considered one of the most devastating neoplasms, showing high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemotherapy.
After the seminal paper of Jacobsson et al. Interestingly, CBD did not affect viability of non-transformed primary glial cells [ 38 ]. When tumour xenografts were generated in immune-deficient mice, in vivo intratumoural treatment with CBD significantly reduced tumour growth [ 37 ].
The anti-proliferative effect of CBD was cannabinoid and vanilloid receptors independent. More importantly, this paper demonstrated for the first time that the anti-tumour effect of CBD involved the induction of oxidative stress, through increased early production of ROS, depletion of intracellular glutathione and increased GSH-associated enzymatic activity.
Accordingly, the CBD anti-proliferative effect was reversed by the anti-oxidant , tocopherol. In line with this, more recently Torres et al. These effects were not observed with either compound individually, indicating them as a prerogative of combination treatment. Differently from Marcu's data [ 39 ], our recent results Dr. Valenti, University of Insubria, Varese, pers. Thus, inhibition of these three molecules appears as part of the multiple molecular targets for CBD anti-neoplastic activity [ 41 ].
Further biochemical analysis of glioma tumour tissues excised from nude mice treated in vivo with CBD indicated a significant decrease of activity and content of 5-LOX, as well as a marked stimulation of FAAH and a decrease of AEA content [ 42 ]. Besides cell growth, CBD reduced glioma cell migration [ 43 ] and invasiveness in a Boyden chamber test [ 39 ], at concentrations lower than those required to inhibit cell proliferation.
CBD seems to counteract glioma cell proliferation and invasion through multiple mechanisms, as summarized in Figure 4. Schematic representation of the signalling pathways associated with CBD effects on glioma. They demonstrated that CBD treatment induced apoptosis, through caspase-3 activation in human acute myeloid leukaemia HL cell line, whereas it had no effect on human monocytes from normal individuals.
Later on, McKallip et al. In Jurkat cells, CBD exposure resulted in the activation of caspase-8, -9, and -3, the cleavage of poly ADPribose polymerase and the decrease in full-length Bid, suggesting a possible cross-talk between the intrinsic and extrinsic apoptotic pathways.
Moreover, exposure to CBD led to the loss of mitochondrial membrane potential and subsequent release of cytochrome C. Finally, CBD decreased the levels of phospho-p38 mitogen-activated protein kinase [ 45 ], and this effect was blocked by treatment with a CB 2 -selective antagonist or ROS scavenger. In addition, CBD treatment caused a significant reduction in tumour burden and increased the level of apoptotic tumours in ELbearing mice [ 45 ]. Together, the results suggest that CBD, acting through CB 2 receptors and ROS production, may represent a novel and highly selective treatment for leukaemia.
Moreover, previous evidence indicated that human leukaemias and lymphomas expressed significantly higher levels of CB 2 receptors compared with other tumour cell lines, suggesting that tumours of immune origin may be highly sensitive to the CB 2 -mediated effects of CBD [ 46 ]. Given the poor response of lung cancer to available therapy and its aggressive biological nature, a series of targets and new therapeutic strategies for their treatment are currently being investigated [ 47 — 50 ].
Recently, Ramer et al. Interestingly all these cellular events were blocked by cannabinoids or TRPV1 receptor antagonists. The significant inhibition of A cell invasion following CBD treatment was also accompanied by the downregulation of another important factor involved in the regulation of cell spreading, the plasminogen activator inhibitor PAI-1 [ 52 ].
Additionally , in vivo studies in thymic aplastic nude mice revealed a significant inhibition of A lung metastases following CBD treatment [ 51 ] and a significant downregulation of PAI-1 protein was demonstrated in A xenografts of CBD-treated rats [ 52 ].
It is worth noting that CBD decreased invasiveness in a range of therapeutically relevant concentrations 0. Together, these findings provide a novel mechanism underlying the anti-invasive action of CBD on human lung cancer cells and imply its use as a therapeutic option for the treatment of highly invasive cancers.
Thyroid cancer is the most common endocrine malignancy and Ligresti et al. Later on, Lee et al. The presence of N-acetyl-L-cysteine NAC , a precursor of glutathione, markedly attenuated the induction of apoptosis and restored the diminished levels of cellular thiols. The observation that CBD induced oxidative stress in thymocytes, EL-4 cells and splenocytes [ 56 ] substantiates the notion that, unlike monocytes, T cells both primary and immortalized, are all sensitive and respond similarly to CBD, with a central role of ROS generation.
Colon cancer is a major cause of morbidity and mortality in Western countries. A recent paper from Izzo's group [ 57 ] demonstrated the chemopreventive effect of CBD in a preclinical animal model of colon cancer based on azoxymethane AOM administration in mice.
In vitro studies, supported the beneficial effect of CBD. In the light of its safety records, these results suggest that CBD might be worthy of clinical consideration in colon cancer prevention.
Angiogenesis consists of the formation of new blood vessels from pre-existing ones and represents another promising therapeutic target for cancer therapy. Surprisingly, so far no study has investigated the effect of CBD on angiogenesis. Our data currently awaiting publication [ 58 ] demonstrated that CBD potently inhibited HUVE cells proliferation, migration and invasion through the induction of endothelial cell cytostasis without triggering apoptosis. Interestingly, CBD also affected endothelial cell differentiation into tubular capillaries as well as the outgrowth of capillary-like structures from HUVEC spheroids in vitro.
In addition, the anti-angiogenic properties of CBD were demonstrated also in vivo , using a matrigel sponge model. Collectively , these preliminary data demonstrate that, besides its well known pro-apoptotic anti-proliferative and anti-invasive actions, CBD may also exert anti-angiogenic effects, thus further strengthening its potential application in cancer therapy. Collectively, the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumours and may also exert anti-migratory, anti-invasive, anti-metastatic and perhaps anti-angiogenic properties.
On the basis of these results, evidence is emerging to suggest that CBD is a potent inhibitor of both cancer growth and spread. Interestingly , the anticancer effect of this compound seems to be selective for cancer cells, at least in vitro , since it does not affect normal cell lines. The efficacy of CBD is linked to its ability to target multiple cellular pathways that control tumourigenesis through the modulation of different intracellular signalling depending on the cancer type considered.
The most common effect of CBD is the increase in ROS production that seems to be determinant for triggering its beneficial action in all the considered cancer cell types. In some cases lung, leukaemia, colon a clear contribution of these receptors has been demonstrated through the use of specific antagonists, but in other cancer types glioma and breast their relevance appears only marginal or absent.
Besides the in vitro data, the efficacy of CBD in reducing tumour growth and, in some cases, metastasization was confirmed in experimental animal models. However, the potential clinical application of CBD for cancer therapy needs some consideration. Its low toxicity is certainly a good starting point.
The route of administration appears more problematic since CBD oral absorption is slow and unpredictable. Interestingly, this range of concentration was demonstrated to be active in inhibiting lung cancer cell invasion [ 52 , 53 ], thus suggesting that in some cases the oral route could be the appropriate choice. Moreover, oromucosal administration may represent a first choice in the presence of nausea and vomiting.
In the light of its safety record and considering that CBD is already currently used in patients with multiple sclerosis, the findings here summarized suggest that CBD might be worthy of clinical consideration for cancer therapy. National Center for Biotechnology Information , U.
Cannabidiol as potential anticancer drug
So, if I was diagnosed with brain cancer, I might try to use CBD oil along with a whole host of things, depending on the staging and my strength and access to. What is the best way to make cannabis oil with both CBD and THC for cancer? for a number of cancer types including lung, glioma, thyroid, lymphoma, skin. Read about cannabis and cancer, and how to find reliable information online.