The cannabinoid agonists HU-210 and JWH-133 promoted glial differentiation in a CB receptor-dependent manner. Moreover, cannabinoid

challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo.255 The nonpsychoactive cannabidiol triggered caspase activation and oxidative stress in human glioma cells.256 Human melanomas express CB1 and CB2 cannabinoid receptors. Activation of these receptors decreased growth, proliferation, angiogenesis, and metastasis, and increased apoptosis, of melanomas in mice.257 THC, through activation of Inhibitors,research,lifescience,medical CB2 cannabinoid receptors, reduced human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. THC arrested cells in G2M via downregulation of Cdc2.258 Cannabinoids induced apoptosis of pancreatic tumor cells via stress protein p8 and endoplasmic reticulum stress-related genes. These effects were prevented by blockade of the CB2 Inhibitors,research,lifescience,medical cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo.259 THC-induced apoptosis in Jurkat leukemia T cells was found to be regulated by translocation of Bad to mitochondria.260 Exposure of leukemia cells to CBD led to CB2-mediated reduction

in cell viability and induction in apoptosis (although CBD is considered not to bind Inhibitors,research,lifescience,medical to either CB1 or CB2 receptors). It is Tyrphostin AG-1478 noteworthy that CBD exposure led to an Inhibitors,research,lifescience,medical increase in reactive oxygen species (ROS) production as well as an increase in the expression of the NAD(P)H oxidases Nox4 and p22(phox).261 Cannabinoid-induced apoptosis of human prostate cancer cells LNCaP proceeded through sustained activation of ERK1/2 leading to Gl cell cycle arrest.262 Rimonabant inhibited human breast

cancer cell proliferation through a lipid raft-mediated mechanism.263 In a pilot phase I trial, nine patients with recurrent glioblastoma multiforme, that had previously failed standard therapy (surgery and radiotherapy) and had clear evidence Inhibitors,research,lifescience,medical of tumour progression, were Histone demethylase administered THC intratumorally. THC inhibited tumor-cell proliferation in vitro, decreased tumor-cell Ki67 immunostaining and prolonged the survival time of two of the patients.264 Conclusion Many drugs used today can cause addiction and are misused and abused, for example opiates,265 cocaine,266 benzodiazepines,267 barbiturates,268 cholinergic agonists,269 ketamine,270,271 dopaminergic agonists,272 amphetamines,273 and others. Nevertheless they are still an important part of our pharmacopeia. Marijuana was used for centuries as a medicinal plant, but during the last century, because of its abuse and addictive potential it was taken out of clinical practice. Now, we believe that its constituents and related compounds should be brought back to clinical use.