What We Know About Cannabis and Cancer

After years of denial, the National Institute of Drug Abuse has finally admitted that marijuana does kill certain cancer cells – including those cells in brain tumors. Marijuana has also been found to reduce the size of other tumors, which is not completely possible with cancer chemotherapy/radiation therapies.

The possibility of marijuana-based anticancer treatment has been around since the mid-1970s, which was coined by a study that reported potential antitumor (Lewis lung adenocarcinoma) properties of marijuana components such as cannabinol, delta9-tetrahydrocannabinol (delta9-THC), and delta8-tetrahydrocannabinol (delta8-THC).

Invivo and invitro tumor model studies have shown that cannabinoids cause tumor shrinkage by arresting the cell cycle, preventing cell survival mechanisms, and activating programmed cell death (apoptosis) in the tumor cells. These actions are elicited by influencing vital cell-signaling pathways, including proapoptotic pathways, in addition to hormone and growth-factor receptor modulation.

One notable study has reported some important anti-tumorigenic mechanisms of cannabinoids – such as inhibition of cell migration, tumor angiogenesis, cell migration and adhesion, invasion of extracellular matrix and related structures and metastatic processes. Unlike conventional anticancer therapy, cannabinoids elicit these actions without harming normal cells.

The available research evidence points out that active principles of marijuana can kill the cancer cells by inducing apoptosis and autophagy mechanisms in addition to the above said molecular mechanisms. In the pre-clinical studies, it has been shown that THC and CBD, as complimentary treatment therapy with radiotherapy, can effectively treat high-grade glioma, which is the deadliest form of brain cancer. As reported in the study, a low dose of THC and CBD is as effective as a high dose in killing cancer cells. Therefore, the risk of unwanted side effects can be eliminated. We already know that radiotherapy cannot completely eliminate cancer cells. THC and CBD can act synergistically  and eliminate cancer cells by two main pathways, namely by inducing apoptosis in the cancer cells or by autophagy mechanisms.

• Apoptosis – A programmed cell death process by which a cell commits suicide upon aging, exposure to physical, chemical or biological insults etc. A typical cancer cell evades apoptosis and survives indefinitely.
• Autophagy – A normal cellular degradation pathway to clear destructed or damaged cells to maintain normal cell functioning, new cell formation, and cell turnover. In cancer cells, defects in autophagy function can help the malignant cells to survive for prolonged period. Induction of autophagy and cancer cell destruction can be achieved by eliciting stress (ER-stress/endoplasmic stress) in cancer cells.

The study found that cannabinoids exposed cancer cells are more sensitized to the effects of radiation. Likewise, chemotherapy and/or radiotherapy can make the cancer cells sensitive to THC and CBD. Other recent studies have reported similar results.  

One such study that investigated the anti-cancer benefits of cannabinoids in two human glioma cell lines has confirmed the anticancer effects of THC and CBD are dose-dependent, as any like therapeutic drugs. Meaning, it can be both cytotoxic (killing cancer cells) and cytostatic (preventing tumor cell growth).

Purified THC and CBD molecules bind to cannabinoid receptors 1 & 2 and activate several intracellular signaling pathways that regulate cellular proliferation. THC has higher affinity to CBD-1 & 2 receptors, while CBD has little affinity; however, the latter antagonize binding of other molecules with these receptors. Hence, the occurrence of THC-mediated adverse events can be minimized.

It is still unclear whether the action of cannabinoids is entirely based on their respective receptor binding action and specific binding affinities. Due to heterogeneity in the intrinsic proteins that are impacted by the cannabinoids, the drug’s effect can be both independent and dependent of receptors.

In cancer cell lines AKT over-activation has been reported, which is believed to be the cause of cellular proliferation (uncontrolled cell growth) and enhanced drug resistance (evasion of sensitivity to treatment medications). AKT is a kinase-pathway that is predominantly involved in the PI3K/AKT/mTOR signaling pathway that regulates vital cellular processes including cell growth, proliferation and survival, neovascularization (blood supply to tumors), invasion and cell migration. Although these pathways are an attractive target for anti-cancer medications, the resistance is still common due to constantly evolving/mutating nature of the cancer cells. Hence, it is important to target the cancer cells holistically by inhibiting tumorigenesis, angiogenesis and metastasis  – all of which can be achieved by cannabinoids.

In laboratory studies, cannabinoids downregulate AKT over-activation in cancer cell lines and exert cancer-killing action by ER-stress pathway activation. In this study, the elicitation of cannabinoids-induced ER-stress response was observed (expression of stress genes such as TRB3 and p8) and analyzed by microarray studies.

ER-stress pathway is a protective form of stress that can be activated as a result of physiological and pathological insults. In cancer cells, excessive ER-stress can turn-on the cell’s pro-apoptotic signaling pathways and triggers cell death, which is quite uncommon with conventional anti-cancer therapies.

The available research evidences point out the irrefutable involvement of cannabinoids on key intracellular signaling pathways such as MAPK, the PI3-kinase/AKT pathway, ER-stress pathways, etc  – which are the vital regulatory pathways of cell cycle, tumorigenesis, and metastasis.

To achieve maximum clinical benefits and cancer remission, cannabinoids can be employed as a combined therapy with radiotherapy and/or chemotherapy such as Temozolomide.

In the same study, the researchers have found that cannabinoid treatment has increased the cells’ sensitivity to radiation and can aid tumor suppression. It is believed that cannabinoids can interfere and delay the post-irradiation DNA repairing mechanisms, and make the radiated cells commit suicide (apoptosis as a result of physical insult or irradiation). Although the complete anti-tumoral mechanism of action of cannabinoids is not yet fully understood, it is believed that the cannabinoid-induced apoptosis depends on increased generation of free radicals or reactive oxygen species that can lead to ER-stress, caspase cascade activation (apoptosis inducer) in the glioma cells and eventual cell death.

Notably, radiation therapy along with cannabinoids has induced autophagy in the glioma cells invitro.

You may worry about undergoing radiation therapy and/or chemotherapy, as it can cause vomiting or nausea, pain, loss of appetite, etc. Several studies have claimed that marijuana’s bioactive constituents can normalize radiation therapy and chemotherapy-induced appetite, reduce nausea and vomiting, pain, inflammation and neurological problems such as numbness, tingling, and muscle weakness without causing serious side effects.

Cancer is an extremely complex disease and cancer cells possess the unique ability to change often, adapt or mutate in extreme environments  –  which help the cells to become resistant and survive through conventional therapies. Combining cannabis-based treatment with conventional anti-cancer approaches can be a multi-pronged attack on treatment-evading cancer cells to achieve complete remission and treatment success.

These findings can pave the way for a new treatment strategy for glioma patients.