Cancer is the second leading cause of death worldwide and, was responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths are due to cancer (WHO). Approximately 70% of deaths from cancer occur in low- and middle-income countries. Around one third of deaths from cancer are due to the 5 leading behavioural and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use. Tobacco use is the most important risk factor for cancer and is responsible for approximately 22% of cancer deaths.
Cancer is a multistep disease characterized by a formation of a preneoplastic lesion (initiation process) which, over time, unless destroyed by the body’s immune system, progresses into malignant tumour. Generally, cell transformation is a combination of intrinsic genetic factors and external exposure to physical, chemical, and biological carcinogens. However, it must be emphasised that ageing and lifestyle are fundamental factors for the development of the disease. Indeed, the incidence of cancer rises dramatically with age, probably due to the decreased efficacy of cellular repair mechanisms, while tobacco, alcohol, an unhealthy diet and, physical inactivity are major global cancer risks. Recent evidence demonstrates that chronic inflammation, independent of the triggering agent, could be responsible of almost 20% of human cancers1. Inflammation itself is a natural body process to remove unhealthy cells or infections as part of the innate immune system and is normally self-limiting. However, the western phenomenon of metabolic syndrome can create persistent and deregulated inflammation which is then associated with an increased risk of malignant diseases2.
Since many studies report chronic inflammation, infection and irritation as a precursor to tumour formation and progression3, it has become of interest to study ways to combat this. One of the main cannabinoids in Cannabis Sativa (C. sativa), Cannabidiol (CBD) has been shown to diminish inflammation, tumour proliferation and induce apoptosis (programmed cell death, a natural process to remove unhealthy cells) in tumour cells of various tumour types, including breast, lung, colon, brain4. It is clear that cannabinoids are powerful inflammatory modulators and most probably function through a complex mechanistic interplay5.
The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen and as a modulator, which can act in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB1 and CB2. There are conflicting reports regarding the ability of CBD to prevent tumour progression however and more research is justified to clarify this issue and help those taking it to determine their best possible outcome with cancer6.
In animal models, CBD has been shown to inhibit the progression of several cancer types. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes on different cell types. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity6.
Historically, cannabinoids have primarily been used as palliative care agents in oncology. However, the various components of the endocannabinoid system (ECS), such as the cannabinoid receptors (CBRs), cannabinoid ligands, and their signalling network are interlinked with several tumour-related states, both as favourable and unfavourable factors. This vast network of molecules is an attractive pharmacological target, and its full potential is yet to be reached. Understanding the specific ways ECS components can regulate the cell cycle, proliferation and cell death considering their interactions with the immune system is necessary for advancing the current state of the art cannabinoid-based anti-cancer therapeutic approaches.
Transplantation and graft versus host disease – recent studies have reported a therapeutic for CBD in transplant acceptance, diminishing the development of graft versus host disease after haematopoeitic stem cell transplants7.
Cannabis and its biologically effective derivatives warrant additional research, ideally, controlled trials in which the cannabidiol and the delta-9-tetrahydrocabinol (THC) strength and use are controlled and documented.
The use of ECS components as anti-cancer agents and targets, and the range of effects they might induce (cell death, regulation of angiogenesis (the formation of blood vessels) and invasion or anticancer immunity), depend largely on the specific cannabinoid ligand acting in a specific cancer cell type. The role of cannabinoids like CBD have been studied in a variety of cancer types: breast cancer; gastro-intestinal; gynaecological; thoracic; prostatic; thyroid and central nervous system malignancies. Although an attractive target, the use of ECS components, like CBD, in anti-cancer treatment is interlinked with many legal and ethical issues that need to be considered. The legislation which outlines the permissive boundaries of their therapeutic use in oncology is still unable to follow the current scientific burden of evidence, but the number of ongoing clinical trials might tip the scale forward in the near future and it is hoped that clear evidence that CBD can help treat cancer of some types, will emerge in the not too distant future8.
- Kundu and Y. J. Surh (2008) Inflammation: gearing the journey to cancer. Mutat. Res, 659, pp. 15–30.
- Mantovani, P. Allavena, et al. (2008) Cancer related inflammation. Nature 454; 7203; pp. 436–444.
- Grivennikov S.I., Greten F.R. & Karin M. (2010) immunity, inflammation and cancer. Cell 140(6) pp883-899.
- Namdar D. Koltai H. (2018) medical cannabis for the treatment of inflammation. Nat. Prod. Commun 13; pp249-254
- Bushlin I, Rosenfield R., Devi L.A. (2010) cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr. Opin. Pharmacol. 10(1); 80.
- Pellati F, Borgonetti V et al. (2018) Cannabis sativa and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer. BioMed Research Int. Vol. 2018, ID 1691428, pp 1-15
- Yeshurun M. et al (2015) Cannabidiol for the prevention of Graft-versus-Host-Disease after allogeneic hematopoietic cell transplantation: Results of a Phase II study. Biol. Blood Marrow Transplant. 21(10) pp1770-1775.
- Moreno E., Cavic M. (2020) The Interplay between Cancer Biology and the Endocannabinoid System—Significance for Cancer Risk, Prognosis and Response to Treatment. Cancers (Basel). 12(11): 3275.