טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentPeled Ella
SubjectThe Role of Cannabinoid Receptors in the Antitumor Effect
of Cannabis
DepartmentDepartment of Biology
Supervisor Dr. David Meiri
Full Thesis textFull thesis text - English Version


Abstract

The therapeutic potential of phytocannabinoids, the main active compounds of the Cannabis plant, has been recently rediscovered in the area of cancer research. More than 120 phytocannabinoids have been identified in the Cannabis plant. A few specific cannabinoids have been proposed as having therapeutic potential for various diseases, including cancer. The majority of studies focus only on the Δ9THC's and CBD's anti-tumor effects, while various cannabinoids and other compounds in the Cannabis plant have been poorly studied with regard to their potential anticancer effects. While many cancer patients are currently treated with whole Cannabis extracts for palliative purposes, there is a need for data concerning Cannabis-mediated antitumor effects.

The current research utilized several methods to assess Cannabis’s effects on cancer cell apoptosis, cell proliferation, and cell viability. AnnexinV analysis, caspase-3 immunofluorescence assay and caspase-3 expression in Western blot analyses were used to assess apoptosis, ki67 immunofluorescent assay was used to assess proliferation and PI-Hoechst detection was used to assess viability. 

Phytocannabinoids’ antitumor effects may be mediated by several GPCR cannabinoid receptors as they have been shown to bind to: CB1, CB2, GRP55, and some transient receptor potential channels, namely TRPV1, TRPV2, TRPA1 and TRPM8. The current research found these receptors to be differentially expressed in various cancer cell lines and we showed that whole Cannabis extracts as well as purified phytocannabinoids induce antitumor effects on specific cancer cells. We also described how these antitumor effects are mediated by CB1 and GPR55 receptors. 

Previous studied have shown synergistic effects of Cannabis compounds suggesting that the administration of several cannabinoids could act synergistically to inhibot tumor growth. This research reveals that whole plant Cannabis extracts are more potent inducers of apoptosis than individual, purified phytocannabinoids.  In addition, we found that Cannabis reduces cell viability of various cancer cells, as well as induces apoptosis in a dose-dependent manner in A549 lung carcinoma cells. Moreover, we demonstrated for the first time a dose-dependent inhibition of A549 cell proliferation upon Cannabis treatment.

This research suggests the intracellular mechanisms involved in Cannabis anti-tumor effects, as some of the Cannabis treatments lead to ERK phosphorylation via the CB1 receptor. Our results suggests that pro-apoptotic effects of Cannabis are mediated by CB1 receptor, whereas the anti-proliferative effects of Cannabis are mediated by GPR55 receptor.

Collectively this research sheds light on the anti-tumor promoting role of whole Cannabis extracts, and the involvement of CB1 and GPR55 in mediating these pro-apoptotic and anti-proliferative effects in lung carcinoma cells. These observations provide preclinical proof-of-concept that whole Cannabis extracts rather than purified cannabinoids could serve as an anti-tumor therapy, at least for lung carcinoma. Overall, our research provides valuable insights regarding the use of Cannabis treatment in cancer. These results will be useful for the optimization of preclinical cannabinoid-based therapies and preliminary clinical testing, which are both currently underway.