Cannabis -vs- Neuroblastoma
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171598: Recently cannabinoid's role has been explored in the area of cancer research. Cancer is caused by uncontrolled proliferation of cells and the ability of these cells to invade into other tissues and spread. Anti-cancer agents function as apoptotic, cell cycle defective or DNA damage agents. A major discovery in cancer in cannabinoid use in cancer treatment is its ability in targeted killing of tumors. Several preclinical studies suggest that Δ9-THC, other naturally occurring cannabinoids, synthetic cannabinoid agonists and endocannabinoids have anti-cancer effects in vitro against lung carcinoma, gliomas, thyroid epithelioma, lymphoma, skin carcinoma, uterine carcinoma, breast cancer, prostate carcinoma, pancreatic cancer and neuroblastoma . These findings were also supported by in vivo studies and the majority of effects of cannabinoids are mediated via CB1 and CB2. The transient receptor potential vanilloid type 1 (TRPV1) has been described as an additional receptor target for several cannabinoids. In addition, the palliative effects of cannabinoids include inhibition of nausea and emesis which are associated with chemo- or radiotherapy, appetite stimulation, pain relief, mood elevation and relief from insomnia in cancer patients. Synthetic THC (Marinol, Dronabinol) and its derivative nabilone (Cesamet), as well as Sativex, have been approved in several countries to control nausea and cancer-related pain in cancer patients undergoing chemotherapy [11-12]. In this review article we focused on the role of cannabionds in different cancer types and the respective signaling pathways.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366283: In addition to signaling through cannabinoid receptors, cannabinoids, in particular anandamide and cannabidiol, have CB receptor-independent effects. AEA and other lipids have been shown to activate TRPV1 . AEA has been shown to induce neuroblastoma, lymphoma, and uterine cervix carcinoma cell death through vanilloid receptors [51, 52]. In addition, inhibition of cancer cell invasion through TIMP1, an inhibitor of metalloproteinases, by methanandamide (AM-356), a hydrolysis resistant AEA analog, is mediated by TRPV1 . It has also been proposed that lipid rafts, membrane domains rich in sphingolipids and cholesterol, mediate AEA effects through CB1 signaling [53, 54]. In cholangiocarcinoma, the anti-proliferative and pro-apoptotic action of AEA is facilitated by lipid raft stabilization, ceramide accumulation, and recruitment of FAS and FAS ligand into lipid rafts .
Another cellular protein that may be important in CB receptor-independent cell death induced by endocannabinoids is COX-2. COX-2 metabolizes AA to prostaglandins (PGs) and elevated levels of both COX-2 and PGs have been measured in neoplastic tissues. COX-2 is also capable of metabolizing AEA to prostaglandin ethanolamides (PG-EAs) and 2-AG to glycerol prostaglandins (PG-Gs) [56, 57]. AEA inhibits growth and induces apoptosis in the colon carcinoma cell lines HT29, a moderate COX-2 expressor, and HCA7/C29, a high COX-2 expressor . AEA also inhibits growth and induces apoptosis in COX-2 transfected tumorigenic keratinocytes, but has little effect on the very low COX-2 expressing colon carcinoma cells SW480 and HaCaT keratinocytes . Apoptosis induced by AEA in human neuroglioma cells is COX-2 mediated and not affected by antagonists of the cannabinoid receptors or TRPV1 . In human neuroblastoma and C6 glioma cells AEA induces apoptosis through a vanilloid receptor mediated increase in intracellular calcium concentration, which activates COX-2, releases cytochrome c and activates caspase 3 .
An important molecule for studying cannabinoid receptor-independent effects is cannabidiol. Cannabidiol is a cannabinoid analog that has no activity at CB1 or CB2 receptors and lacks psychotropic effects. Cannabidiol has been shown to inhibit glioma and breast tumor growth in vitro and in vivo through induction of apoptosis and inhibition of cell migration and angiogenesis, with these effects being independent of CB and TRPV1 receptor activity [60-62]. Cannabidiol reduces the invasiveness of breast cancer cells by inhibiting Id-1, an inhibitor of basic helix-loop-helix transcription factors involved in tumor progression, at the promoter level . A quinone analog of cannabidiol, HU-331, a highly specific inhibitor of topoisomerase II, has been reported to have high efficacy against human cancer cell lines in vitro and against tumor grafts in nude mice . HU-331 also inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and anti-angiogenic cytokines and their receptors .
Cannabinoids may also interfere with the ability of lysophosphatidylinositol (LPI) to bind to GPR55. LPI induces cancer cell proliferation through GPR55 activation by triggering the initiation of ERK, AKT, and calcium mobilization cascades . The activation of these cell proliferation cascades by GPR55 has been verified using siRNA to block LPI signaling through GPR55 . In addition, pretreatment of breast and prostate cancer cells with cannabidiol or Rimonabant (SR141716A), a CB1 antagonist that also binds to GPR55, blocks the ability of LPI to induce cell proliferation through GPR55 .
http://www.ncbi.nlm.nih.gov/pubmed/27022310: Neuroblastoma (nbl) is one of the most common solid cancers in children. Prognosis in advanced nbl is still poor despite aggressive multimodality therapy. Furthermore, survivors experience severe long-term multi-organ sequelae. Hence, the identification of new therapeutic strategies is of utmost importance. Cannabinoids and their derivatives have been used for years in folk medicine and later in the field of palliative care. Recently, they were found to show pharmacologic activity in cancer, including cytostatic, apoptotic, and antiangiogenic effects.
We investigated, in vitro and in vivo, the anti-nbl effect of the most active compounds in Cannabis, Δ(9)-tetrahydrocannabinol (thc) and cannabidiol (cbd). We set out to experimentally determine the effects of those compounds on viability, invasiveness, cell cycle distribution, and programmed cell death in human nbl SK-N-SH cells.
Both compounds have antitumourigenic activity in vitro and impeded the growth of tumour xenografts in vivo. Of the two cannabinoids tested, cbd was the more active. Treatment with cbd reduced the viability and invasiveness of treated tumour cells in vitro and induced apoptosis (as demonstrated by morphology changes, sub-G1 cell accumulation, and annexin V assay). Moreover, cbd elicited an increase in activated caspase 3 in treated cells and tumour xenografts.
Our results demonstrate the antitumourigenic action of cbd on nbl cells. Because cbd is a nonpsychoactive cannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anticancer drug in the management of nbl.