The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat-Gan, Israel.
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 (Delta(9)-THC) as an essential mediator of cannabinoid antitumoral action. Methods and results. Administration of Delta(9)-THC to glioblastoma multiforme (GBM) cell lines results in a significant decrease in cell viability. Cell cycle analysis showed G(0/1) arrest and did not reveal occurrence of apoptosis in the absence of any sub-G(1) 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 p16(INK4A), 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. Delta(9)-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.
Department of Laboratory Medicine, Divison of Pathology, F46, Karolinska Institutet and Karolinska University Hospital Huddinge, SE 141 86 Stockholm, Sweden.
Endogenous arachidonic acid metabolites with properties similar to compounds of Cannabis sativa Linnaeus, the so-called endocannabinoids, have effects on various types of cancer. Although endocannabinoids and synthetic cannabinoids may have pro-proliferative effects, predominantly inhibitory effects on tumor growth, angiogenesis, migration and metastasis have been described. Remarkably, these effects may be selective for the cancer cells, while normal cells and tissues are spared. Such apparent tumor cell selectivity makes the endocannabinoid system an attractive potential target for cancer therapy. In this review we discuss various means by which the endocannabinoid system may be targeted in cancer and the current knowledge considering the regulation of the endocannabinoid system in malignancy.
Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Delta(9)-Tetrahydrocannabinol (THC) is the primary cannabinoid of marijuana and has been shown to either potentiate or inhibit tumor growth, depending on the type of cancer and its pathogenesis. Little is known about the activity of cannabinoids like THC on epidermal growth factor receptor-overexpressing lung cancers, which are often highly aggressive and resistant to chemotherapy. In this study, we characterized the effects of THC on the EGF-induced growth and metastasis of human non-small cell lung cancer using the cell lines A549 and SW-1573 as in vitro models. We found that these cells express the cannabinoid receptors CB(1) and CB(2), known targets for THC action, and that THC inhibited EGF-induced growth, chemotaxis and chemoinvasion. Moreover, signaling studies indicated that THC may act by inhibiting the EGF-induced phosphorylation of ERK1/2, JNK1/2 and AKT. THC also induced the phosphorylation of focal adhesion kinase at tyrosine 397. Additionally, in in vivo studies in severe combined immunodeficient mice, there was significant inhibition of the subcutaneous tumor growth and lung metastasis of A549 cells in THC-treated animals as compared to vehicle-treated controls. Tumor samples from THC-treated animals revealed antiproliferative and antiangiogenic effects of THC. Our study suggests that cannabinoids like THC should be explored as novel therapeutic molecules in controlling the growth and metastasis of certain lung cancers.
Hebrew University, Pharmacy School, Department of Medicinal Chemistry and Natural Products, Israel.
natalya@md.huji.ac.il
Marijuana has been used in medicine for millennia, but it was not until 1964 that delta9-tetrahydrocannabinol (delta9-THC), its major psychoactive component, was isolated in pure form and its structure was elucidated. Shortly thereafter it was synthesized and became readily available. However, it took another decade until the first report on its antineoplastic activity appeared. In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesis. Antiproliferative action on some other cancer cells was also found. In spite of the promising results from these early studies, further investigations in this area were not reported until a few years ago, when almost simultaneously two groups initiated research on the antiproliferative effects of cannabinoids on cancer cells: Di Marzo's group found that cannabinoids inhibit breast cancer cell proliferation, and Guzman's group found that cannabinoids inhibit the growth of C6 glioma cell. Other groups also started work in this field, and today, a wide array of cancer cell lines that are affected is known, and some mechanisms involved have been elucidated.
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Just to name a few.