Background. The active components of Cannabis sativa L., Cannabinoids, traditionally used in the field of cancer for alleviation of pain, nausea, wasting and improvement of well-being have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory activity and induction of tumor regression. Here we used several experimental approaches, which identified delta-9- tetrahydrocannabinol (Δ9-THC) as an essential mediator of cannabinoid antitumoral action. Methods and results. Administration of Δ9-THC to glioblastoma multiforme (GBM) cell lines results in a significant decrease in cell viability. Cell cycle analysis showed G0/1 arrest and did not reveal occurrence of apoptosis in the absence of any sub-G1 populations. Western blot analyses revealed a THC altered cellular content of proteins that regulate cell progression through the cell cycle. The cell content of E2F1 and Cyclin A, two proteins that promote cell cycle progression, were suppressed in both U251-MG and U87-MG human glioblastoma cell lines, whereas the level of p16INK4A, a cell cycle inhibitor was upregulated. Transcription of thymidylate synthase (TS) mRNA, which is promoted by E2F1, also declined as evident by QRT-PCR. The decrease in E2F1 levels resulted from proteasome mediated degradation and was prevented by proteasome inhibitors. Conclusions. Δ9-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G1 arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Δ9-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.
Bibliographical noteFunding Information:
This work was performed in partial fulfillment of the requirements for M.Sc degree of G.G. from the Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Israel. G.R. holds the Djerassi Chair in Oncology at the Sackler School of Medicine, Tel Aviv University. Gil Galanti and Tamar Fisher contributed equally to this paper.