A Review of the Therapeutic Antitumor Potential of Cannabinoids

Abstract

Objectives:

The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment.

Methods:

A literature survey of medical and scientific databases was conducted with a focus on the biological and medical potential of cannabinoids in cancer treatment.

Results:

Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of “cannabinoid sensitizers.” Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness.

Conclusions:

A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with standard anticancer strategies. With such knowledge, cannabinoids could become a therapy of choice in contemporary oncology.

Introduction

C annabis sativa is an annual plant rich in biologically active chemical compounds—terpenoids, flavonoids, and more than 100 types of cannabinoids. Besides being used as psychotropic substances, cannabis plants have been used for centuries in folk medicine and are under intense investigation for their medical potential.^1
–3

Quantitatively important exogenous cannabinoids from C. sativa are the psychotropic Δ9-tetrahydrocannabinol (Δ9-THC) and the nonpsychotropic cannabidiol (CBD). Δ9-THC is synthesized at significant concentrations in female specimens of cannabis plants used as psychotropic drugs, while CBD predominates in plants grown for fiber. Considering the fact that CBD is also pharmacologically active, both types of plants have potential medical use.⁴

Numerous investigations had identified several dozen other psychotropic and nonpsychotropic active cannabinoids, including cannabidiol, cannabinol, and cannabigerol.^1,5,6

Despite the fact that different cannabinoids exhibit a variety of pharmacological activities, most research attention has focused on studies concerning the impact of cannabis on cancer. Although cancer care specialists are expected to answer patients' questions about the potential anticancer effects of cannabinoids in clinical practice, so far not enough data are available to explain their effectiveness as therapeutic agents.

Materials and Methods

A systematic literature survey of existing scientific databases was conducted for preclinical and clinical oncological investigations of cannabinoid signaling pathways and potential anticancer activities, as well as recent studies of cannabinoids in experimentally and clinically used cancer models.

Mechanisms of Anticancer Activity of Cannabinoids

Cannabinoids have been shown to possess potent anticancer activity in multiple human and animal cancer cells in vitro and in vivo.^5,7,8
–10 These substances are thought to influence tumor growth through various mechanisms, predominantly by induction of cancer cell death or apoptosis, and inhibition of cancer cell proliferation.¹¹

The efficacy of cannabinoid anticancer activity depends on their ability to stimulate autophagy-mediated apoptotic cell death.¹² According to the available literature data, autophagy inhibits malignant transformation in the early stages of tumor development. However, in advanced stages of tumor progression, autophagy provides energy for the increased demands of tumor growth, enabling tumor cells to resist cytotoxic therapy and cell death. A series of experiments conducted on glioma, melanoma, and pancreatic and hepatic cancer cell lines confirmed that activation of autophagy by cannabinoids leads to cell death.^13

–16

According to Salazar et al., binding THC to cannabinoid receptors leads to stimulation of de novo sphingolipid synthesis and triggers pathways, including endoplasmic reticulum (ER) stress-related signaling that consequently promotes autophagy.¹⁷

It has been shown that THC exerts antitumor effects in melanoma cells by autophagy, not only by activation of ER stress but also by TRIB3-dependent inhibition of Akt/mTORC1 signaling, resulting with apoptosis.¹⁴

Moreover, the authors identified stress-regulated protein p8 (a candidate of metastasis) as an essential mediator of cannabinoid antitumor action and demonstrated the proapoptotic role of stress protein p8 itself by upregulation of ER stress-related genes ATF-4, CHOP, and TRB3.¹⁵

Furthermore, an interesting hypothesis given by Massi et al. suggests that the concomitant use of CBD and 5-lipoxygenase (LOX) inhibitors could be very effective in the treatment of tumor growth.¹⁸ Namely, they revealed that CBD (cannabidiol) exerts its antitumor effects through modulation of the procarcinogenic (LOX) pathway, which possesses a fundamental role in cancer development, and fatty acid amide hydrolase (FAAH), the main anandamide-degrading enzyme, while decreasing anandamide content and binding to CB1 cannabinoid receptors. This new model suggests a possible interaction of these routes in the control of tumor growth,¹⁸ expressing U87 cells, compared to wild-type controls.

CBD, which has a relatively low affinity for cannabinoid receptors, also triggers apoptosis via enhanced production of reactive oxygen species (ROS), resulting in an increase in the antioxidant enzyme activity.¹⁸ Moreover, it has been shown in glioma cells that CBD causes a dramatic drop in mitochondrial oxidative metabolism and modulates extracellular signal-regulated kinase (ERK) and ROS pathways associated with apoptosis initiation.^2,19,20 Furthermore, as shown in oral cancer, CBD inhibits oxygen consumption in the mitochondria via receptor-independent mechanisms.²¹

McAllister et al. also reported that cannabidiol modulates signaling patterns related to ERK and ROS.²³ These modulations lead to downregulation of Id-1 expression. It has been shown that Id-1, an inhibitor of basic helix-loop-helix transcription factors, is a key regulator of metastatic potential in cancers. Also, CBD upregulates the pro-differentiation factor, Id-2. The efficacy of CBD was demonstrated on breast cancer cells in vitro through inhibition of invasion, as well in an immune-competent mice model through significant reduction of primary tumor mass and breast metastatic foci. Moreover, reducing Id-1 expression with CBDs could also represent a strategy for treatment of other aggressive cancers since a mechanism for Id-1 upregulation and consequent progression has been found in almost all solid tumors.^22
–24

In summary, cannabinoid treatment of tumor cells modulates signaling pathways inducing cell cycle arrest, apoptosism and/or inhibition of angiogenesis and metastases.^7,25,26 In addition to modulating a variety of physiological processes in the cell, cannabinoids and their receptors are also involved in many processes important in cancer cells, such as proliferation, invasion, adhesion, and motility.² Through all these processes, cannabinoids exert antitumor activity, suggesting their possible application as antineoplastic agents.^22,27

Exogenous Cannabinoids

It is well known that the most biologically active exogenous cannabinoids Δ9-THC and CBD, as well as some synthetic cannabinoids, have different affinities for CB receptors.^{1

–5,28

–34} However, it is important to emphasize that in addition to receptor-dependent activities, cannabinoids may also act through receptor-independent pathways.^35,36 For example, CB1 may activate cellular signal transduction pathways associated with the suppression of adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs).³⁵ Furthermore, selective CB1 agonists without immunosuppressive and psychotropic cannabinoid effects may be useful as antineoplastic drugs in a large number of tumor types. It has been shown that the antineoplastic activity of synthetic cannabinoids in vitro and in vivo depends on their chemical structures, cancer type, and the therapeutic protocol applied.^37
–39

Synthetic THC medications may have several off-label uses in the clinic, such as Alzheimer's disease agitation, moderate-to-severe spasticity, or neuropathic pain in multiple sclerosis. Synthetic THC pharmaceutical medications, such as dronabinol or nabilone, are indicated to treat nausea and vomiting associated with chemotherapy and AIDS wasting syndrome.⁴⁰

Endogenous Cannabinoids

Mammalian cells synthesize their own endocannabinoids which, together with their cognate receptors and downstream signaling pathways constitute an endogenous cannabinoid system.^41

–46 The function of endogenous cannabinoids is finely modulated by physiological and pathological processes, where transient increases in endocannabinoid levels represent an adaptive response to restore perturbed homeostasis under acute pathological conditions.³⁶ The predominant role of endogenous cannabinoids is neuromodulation of brain cells and peripheral neurons, where they play a significant role in extraneural sites, serving as autocrine and paracrine mediators, and in controlling processes such as immunomodulation, peripheral pain, vascular tone, or intraocular pressure.^7,35,36

Cancer-Related Studies of Cannabinoids

Preclinical and clinical investigations

Preclinical studies on different models mostly show that cannabinoids reduce tumor progression. Moreover, cannabinoids are found to possess selectivity for specific cancer cells,^2,10 while at the same time protecting healthy tissue from cell death.^7,47 This selectivity was first demonstrated in glial cells, both in vitro and in experimental animals, and is considered to be associated with the expression of CB1 and CB2, as well as other receptors, and with the activation of nonreceptor signaling pathways associated with specific types of tumor cells.^48
–50

In vitro studies

The antiproliferative effects of cannabinoids have been investigated in vitro on a large panel of cell lines by several teams. In various studies, it was stated that cannabinoids, by stimulating CB1, CB2, or both types of receptors inhibit the proliferation and invasion of breast cancer cells in vitro. ^10,18 Δ9-THC decreases invasion and viability in a time- and concentration-dependent manner in HeLa cells through interactions with CB1, CB2, and transient receptor potential cation channel subfamily V member 1 receptors (TRPV1).^51,52

In vitro investigations of human non-small cell lung cancer using A549 and SW-1573 cell lines demonstrated the presence of CB1 and CB2 cannabinoid receptors and suggest that THC affects epidermal growth factor-induced cell proliferation, chemotaxis, and chemoinvasion. These THC-mediated effects are achieved by phosphorylation of ERK1/2, c-Jun N-terminal kinases (JNK1/2), serine/threonine protein kinases (AKTs), and focal adhesion kinase (FAK) at tyrosine 397.⁵³

Investigations of human colorectal carcinoma cells suggest that both cancerous and normal colonic tissue possess CB1 and CB2 receptors at the mRNA and protein levels. Active components of cannabis protect DNA from damage caused by oxidative stress and exert antiproliferative activity in colon cancer cells through various mechanisms involving not only CB1 and CB2 but also TRPV1 and peroxisome proliferator-activated receptors (PPARγ).^28,29

Cannabinoids display potent anticancer activity against tumor cells that express high resistance to standard chemotherapeutics, such as gliomas,^15,16 pancreatic adenocarcinomas,⁵⁴ and hepatocellular carcinomas.⁵⁵

In a study investigating the antitumor effects of synthetic cannabinoids, Qamra et al. concluded that synthetic cannabinoids, CB1 and CB2 agonists, modulate cyclooxygenase-2 inhibitors (COX-2)/prostaglandin E2 (PGE2) signaling pathways in breast cancer cells in vitro.³⁷

Also, a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB2 may modulate breast tumor growth and metastasis in vitro by inhibiting signaling of chemokine receptor type 4 (CXCR4) and its ligand stromal cell-derived factor-1 (SDF-1). This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.³⁸

In vivo studies

The antitumor activity of cannabinoids has been demonstrated in various in vivo tumor models. For example, an in vivo study conducted on mice bearing human glioma tumors followed the anticancer activity of CBD- and THC-loaded poly-ɛ-caprolactone delivered in continuous release polymer microcapsules.⁵⁶ Also, the antitumor activity of cannabidiol was monitored in mice with induced primary breast carcinomas and lung metastases.²⁰ Here, the authors showed that cannabidiol applied in this manner is associated with a reduction in the growth of primary tumors, as well as in the size and number of lung metastatic foci.^20,56 Further, an in vivo study on immunodeficient mice carriers of non-small lung carcinoma revealed significant growth inhibition of primary tumors and lung metastases in animals treated with THC. Use of immunohistochemical techniques on tumor samples also support the antiproliferative and antiangiogenic effects of THC.⁵³

Although many studies have reported the antitumor potential of cannabinoids, there are also some conflicting results in the literature. In mice injected with 4T1 tumor cells, THC administration was found to increase local tumor size and the number and size of metastasis. The authors proposed that THC suppresses an antitumor immune response mediated by CB2.⁵⁷

Adjuvant properties of cannabinoids in cancer treatment

Few preclinical studies have investigated the possible combined effects of cannabinoids and standard radiation therapy or chemotherapeutics. However, reports investigating “cannabinoid sensitizers” suggest that cannabinoids could increase the efficacy of classical oncological treatment methods.¹² In a study that investigated the possible synergy between γ irradiation and the non-psychotropic cannabinoids, cannabidiol (CBD) and cannabidiol-dimethylheptyl (CBD-DMH), an increased incidence of cell death in HL-60 leukemic cells was shown.^58,59

Moreover, Liu et al. have shown that there is a synergistic interaction between THC and chemotherapy in leukemic cells in vitro. In addition, exposure of cells to sublethal levels of THC sensitizes cells to cytotoxic agents and enhances cell death in vitro. ⁶⁰

Torres et al. showed that combined treatment with temozolomide (TMZ) and submaximal doses of THC reduced the viability of several human glioma cell lines and two primary cultures of human glioma cells. Treatment with low doses of THC and TMZ decreased tumor growth to a much greater extent than treatment with either agent alone in both TMZ-sensitive and TMZ-resistant glioma multiform xenografts.

Also, Torres et al. investigated the ability of combined administration of TMZ and THC+CBD to stimulate glioma cell death in tumor xenografts. Treatment with TMZ and submaximal doses of THC and CBD strongly reduced the viability of U87MG and T98G glioma xenograft cells. Moreover, treatment with TMZ and THC+CBD enhanced apoptosis and autophagy in glioma cells in both TMZ-sensitive and TMZ-resistant tumors. Thus, it is believed that activation of autophagy mechanisms plays a pivotal role in the effectiveness of this drug combination.⁶¹

Clinical trials

Earlier clinical studies regarding the use of cannabinoids have been mainly limited to examination of their palliative action during the application of standard chemotherapeutics to prevent nausea, vomiting, and cachexia, leading to approved pharmaceuticals for these purposes.^62
–64 Given that cannabinoids inhibit pain, there have been clinical trials of pharmaceuticals that would reduce the painful side effects of malignant diseases.⁵⁶ In 2015, there was also an open clinical trial encompassing ∼17,000 patients, confirming the palliative effects of cannabis in terms of improving the quality of life of cancer patients.⁶⁵

Singh et al. described the clinical case of a child with acute lymphoblast leukemia (ALL) in terminal stage, who previously underwent chemotherapy and a bone marrow transplant. Parents decided to start treatment with hemp marijuana oil, 1 mL thrice per day. Although, unfortunately, the child died from bowel perforation 78 days later, the treatment was associated with a significant and concentration-dependent decrease in blasts in whole blood. These results cannot be explained by any other therapies, as the child was only on cannabinoid treatment. Hemp oil treatment has to be viewed as polytherapy since many cannabinoids within the resinous extract have previously confirmed targets and antiproliferative, proapoptotic, and antiangiogenic properties.⁶⁶

However, completed clinical trials confirming the antineoplastic activity of cannabinoids, so far, have only been conducted on a small number of subjects. In the first and only clinical study completed before 2016, the effect of intracranial THC administration was investigated on a cohort of nine patients with terminal stage glioma multiforme. While no conclusions were drawn by the authors regarding the effectiveness of this treatment, observations of partial regression of tumors in several patients were reported.⁵⁸

Two more clinical trials have been recently completed. The first is a phase I/II trial aimed to evaluate the combined effects of Sativex (oromucosal cannabis extract with THC and CBD in ratio 1:1) and temozolomide in patients with recurrent glioblastoma multiforme (https://clinicaltrials.gov/ct2/show/NCT01812603 and https://clinicaltrials.gov/ct2/show/NCT01812616). The study was completed in 2016, but results are not yet available. The other clinical trial is a phase II study proposed to evaluate the effects of CBD as monotherapy in patients with solid tumors (https://clinicaltrials.gov/ct2/show/NCT02255292). This study was completed in 2015 and results are expected to be summarized in 2017.¹¹

Conclusions

A significant number of cannabinoid compounds have been discovered, developed, and used to study their effects on cancers in model systems. Although numerous investigations have been conducted on cells in vitro, and on experimental animals ex or in vivo, there is a scarcity of clinical trials on the utility of cannabinoids for the treatment of human cancers. Further studies require an even wider range of tests in terms of monitoring the effects of cannabinoids alone or in combination with standard anticancer strategies, both in preclinical and clinical trials. This is necessary to clarify signaling patterns and specific molecular targets, as well as to guide adoption of protocols on the use of different types of cannabinoids and their dosages in relationship to certain types and stages of cancers.

Armed with such extensive knowledge, clinicians will then be able to take advantage of cannabinoids as a powerful therapy of choice in contemporary oncology.

Footnotes

Acknowledgment

We thank Edward T. Petri for editing this article for English language grammar and usage.

Author Disclosure Statement

No competing financial interests exist.

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