Gliomas/Cancer - Medical Marijuana Research Papers Worldwide

Gliomas/Cancer - Medical Marijuana Research Papers Worldwide


"Researchers worldwide have shown that cannabinoids kill cancer cells, by activating their suicide switch and by shutting down of blood supply, while enhancing healing by improving appetite and sleep, all without harmful side-effects, as the following 30 research papers attest." - MMJDoc



1 d9-THC activates apoptosis (programmed cell death) in C6 glioma cells. Guzman et-al 1998. FEBS Letters 436- 6-10.

1 Results thus show that d9-THC-induced apoptosis (programmed cell death) in glioma (brain tumor) glial (neural maintaining) cells may rely on a Cannabinoid-1  receptor-independent stimulation of sphingomyelin breakdown

1 d9-THC - or  Tetrahydrocannabinol, is the main active ingredient of cannabis was shown to activate apoptosis (programmed cell death) in glial (neural maintaining) glioma cells, as determined by DNA fragmentation testing and with loss of plasma membrane asymmetry. d9-THC stimulated sphingomyelin hydrolysis in C-6.9 glioma (brain tumor) cells. d9-THC and N-acetyl sphingosine, a cell-permeable ceramide analog,activated 1 Apoptosis (programmed cell death) in several transformed neural cells, however, not in main astrocytes (neuron assisting cells) or neurons.

1 Although glioma (brain tumor) glial (neural maintaining) cells expressed the Cannabinoid-1  receptor, neither d9-THC-induced apoptosis (programmed cell death) nor d9-THC-induced sphingomyelin breakdown was blocked by SR141716, a specific antagonist of that receptor..



2 The anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation & extracellular signal-regulated kinase activation.Guzman et-al 2000.  Nature Medicine 6- 313-319.

2 These results may provide the foundation for a new therapeutic approach for the treatment of malignant gliomas (brain tumor).

2 d9-THC - Tetrahydrocannabinol is the main active ingredient of cannabis, which has been shown to activate apoptosis (programmed cell death) of transformed neural cells in mammalian cell culture. Here, we demonstrate that intra-tumoral dosing of d9-THC & synthetic cannabinoid agonist WIN-55,212-2 activated a significant regression of malignant brain tumors (glioma) in rats and in rodents that are deficient in recombination activating gene 2. This phytocannabinoid treatment did not yield any substantial neurotoxic effect in the conditions used.

2 Experiments with two subclones of C6 glioma (brain tumor) cells in culture demonstrated that cannabinoids signal apoptosis (programmed cell death) by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation.





3 The inhibition of tumor angiogenesis (formation of new blood cells) by phytocannabinoids. Guzman et-al 2003.  The FASEB Journ.

3 Phytocannabinoids, the active ingredients of Cannabis Sativa L.,  act in the body by mimicking endogenous substances—the endocannabinoids—that activate specific cell surface receptors..... phytocannabinoids exert various palliative effects in cancer patients. In addition, phytocannabinoids inhibit the growth of different types of tumor cells, including glioma (brain tumor) cells, in laboratory animals.

3 They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the constraint of tumor angiogenesis (formation of new blood cells).

3 Of interest, phytocannabinoids seem to be selective antitumoral compounds, as they kill glioma (brain tumor) cells, however, not their non-transformed astroglial counterparts. On the foundation of these preclinical findings, a pilot clinical study of d9-THC - Tetrahydrocannabinol in patients with recurrent glioblastoma multiforme was recently run. The good safety profile of d9-THC, together with its possible growth-constraining action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of phytocannabinoids.




4 The antitumor effects of cannabidiol, a non-psychotropic phytocannabinoid, on human glioma (brain tumor) cell lines.Massi et-al 2004. Journ. of Pharmacology & Experimental Therapeutics Fast Forward 308- 838-845.

4 In this study, we demonstrated that CBD caused a concentration-related constraint of the glioma (brain tumor) cell viability under serum-free conditions to exclude any interaction with the reported direct interaction between serum proteins, such as albumin, and phytocannabinoids. A question could be raised about the relatively high values of IC50 of CBD, found in this work, as compared with the reported more potent d9-THC.

4 It is well known that non psychotropic phytocannabinoids are usually used at higher concentrations either in vitro or in vivo to obtain pharmacological effects, probably due to the relatively low affinity of these compounds for Cannabinoid-1  and Cannabinoid-2 cannabinoid receptors. Importantly, however, our results revealed that compared with d9-THC, which caused a constraint of cell viability during a two- to three-day or four- to five-day period the inhibitory effects of CBD already became apparent after twenty four hours of exposure to the drug.

4 The different potency of CBD versus d9-THC was likewise confirmed in our experimental protocol, where d9-THC affected the viability of our cell lines after 4 days of exposure and with an IC50 of about three to four micro-mole.







5 Phytocannabinoids inhibit the vascular (blood vessel) endothelial growth factor - pathways in gliomas (brain tumor)  Guzman et-al 2004. Cancer Research 64- 5617-5623.

5 Phytocannabinoids mitigate tumor angiogenesis (formation of new blood cells) in rodents, however, the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor - GF (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether phytocannabinoids affect it. As a first approach, the cDNA array analysis demonstrated that phytocannabinoid dosing to rodents bearing sc. gliomas (brain tumor) lowered the expression of various vascular endothelial growth factor - GF pathway-related genes.

5 The use of other protocols provided supplementary information that phytocannabinoids depressed the vascular (blood vessel) endothelial growth factor - GF pathway by decreasing the production of vascular (blood vessel)endothelial growth factor - GF and the activation of VEGF receptor (VEGF (blood vessel growth factor)R)-2, the most prominent VEGF receptor, in cultured glioma (brain tumor) cells and in mouse gliomas (brain tumor). phytocannabinoid-induced constraint of vascular (blood vessel)endothelial growth factor - GF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis.

5 These changes in the vascular (blood vessel) endothelial growth factor - GF pathway were paralleled by changes in tumor size.

5 Moreover, intra-tumoral dosing of the phytocannabinoid d9-THC to two patients with glioblastoma multiforme (grade IV astrocytoma) lowered vascular (blood vessel) endothelial growth factor - GF levels and VEGFR-2 activation in the tumors. Because blockade of the vascular endothelial growth factor - GF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for phytocannabinoid-based therapies.




6 Phyto cannabinoids selectively inhibit proliferation & activate death of cultured human glioblastoma multiforme cells. Allister et-al 2005. Journ. of Neuro Oncology 74- 31-40.

6 Normal tissue toxicity limits the efficacy of current treatment modalities for glioblastoma multiforme (GBM cancer). We evaluated the influence of cannabinoids on cell proliferation, death, and morphology of human GBM cancer cell lines and in main human glial cultures, the normal cells from which GBM cancer tumors arise. The influence of a plant derived cannabinoid agonist,

6 d9-tetrahydrocannabinol = THC, and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy. We discovered that-d9 THC decreases cell proliferation and dial up cell death of human GBM cancer cells more rapidly than WIN 55,212-2. d9-THC was likewise more potent at inhibiting the proliferation of GBM cancer cells compared to WIN 55,212-2.

6 The effects of d9-THC and WIN 55,212-2 on the GBM cancer cells were partially the result of cannabinoid receptor activation. The same concentration of d9-THC that significantly inhibits proliferation and dial-up death of human GBM cancer cells has no significant impact on human principal glial cultures. Evidence of selective efficacy with WIN 55,212-2 was likewise observed however, the selectivity was less profound, and the synthetic agonist yielded a greater disruption of normal cell morphology compared to d9-THC.




7 Combined preclinical therapy of cannabinoids & Temozolomide against glioma (brain tumor). Torres et-al 2011. Molecular Cannabis Therapeutics 10- 90.

7 Here, we show that the combined dosing of d9-THC and chemical temozolomide - TMZ; the benchmark agent for the management of GBM cancer) exerts strong antitumor action in glioma (brain tumor) xenografts, an effect that is likewise observed in tumors that are resistant to temozolomide - TMZ treatment. Combined dosing of d9-THC and temozolomide - TMZ enhanced autophagy, whereas pharmacologic or genetic constraint of this process blocked temozolomide - TMZ + d9-THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination.

7 Administration of submaximal doses of d9-THC and cannabidiol - CBD; another plant-derived phytocannabinoid that likewise activates glioma (brain tumor) cell death through a mechanism of action different from that of d9-THC, remarkably reduces the growth of glioma (brain tumor) xenografts. Moreover, treatment with temozolomide - TMZ and submaximal doses of d9-THC and CBD yielded a strong antitumoral action in both temozolomide - TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined dosing of temozolomide - TMZ and phytocannabinoids could be therapeutically exploited for the management of GBM cancer.




8 A pilot clinical study of d9-THC in patients with recurrent glioblastoma multiforme. Guzman et-al 2006. British Journ. of Cancer

8 d9-THC inhibited tumour-cell proliferation in vitro and lowered tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the foundation for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.




9 phytocannabinoids as a potential new drug therapy for the treatment of gliomas (brain tumor). Parolaro & Massi. 2008. Expert Reviews of Neurotherapeutics 8- 37-49

9 Phytocannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non transformed counterparts. A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the foundation for further studies aimed at better evaluating the potential anticancer activity of phytocannabinoids







10 d9 THC inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Galanti et-al 2007. Acta Oncologica 12- 1-9.

10 d9-THC is shown to significantly affect viability of GBM cancer cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is implied that d9-THC and other phytocannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors

10 Administration of d9-THC to glioblastoma multiforme (GBM cancer) cell lines results in a significant decrease in cell viability. Cell cycle analysis demonstrated G(0/1) arrest and did not reveal occurrence of apoptosis (programmed cell death) in the absence of any sub-G(1) populations. Western blot analyses revealed a d9-THC altered cellular content of proteins that regulate cell progression through the cell cycle.

10 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, likewise declined as shown by QRT-PCR. The decrease in E2F1 levels resulted from proteasome mediated degradation and was blocked by proteasome inhibitors.


Anandamide - Body Endo-Cannabinoid


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11 Expression of phyto cannabinoid receptors & neurotrophins in human gliomas (brain tumor). Caratozzolo et-al 2007. Neurological Sciences 28- 304-310.

11 Recent studies have shown an antitumor activity of cannabinoid-1  and Cannabinoid-2 receptors in gliomas (brain tumor). This effect was mediated by neurotrophins in breast and prostate carcinoma, while in gliomas (brain tumor) this relationship has not yet been considered. The aim of this study was to investigate the expression of cannabinoid receptors Cannabinoid-1  and Cannabinoid-2, neurotrophin NGF and NT-3 and their receptors TrkA and TrkC in glioma and endothelial cells.

11 The analysis was performed in fourteen gliomas (brain tumor) and two non-tumour brain specimens by immunohistochemistry and real-time quantitative-polymerase chain reaction (RTQ-PCR). gliomas (brain tumor) demonstrated a weak immunoreactivity for Cannabinoid-1  and Cannabinoid-2 in tumour and in endothelial cells, and for NGF/TrkA mainly in tumour cells, while a moderate/diffuse immunoreactivity was found for NT-3/TrkC. Cannabinoid-2 was expressed on three out of six low-grade gliomas (brain tumor) and in all high-grade gliomas (brain tumor).

11 Non-tumour brain tissues were weakly positive in astrocytes   (neuron assisting cells) and endothelium for Cannabinoid-1 , Cannabinoid-2, NT-3 and TrkC and negative for NGF and TrkA. By RTQ-PCR, gliomas (brain tumor) demonstrated low mRNA levels of NGF/TrkA and moderate levels of Cannabinoid-1 , NT-3 and TrkC. Cannabinoid-2 mRNA expression was low or absent. A potential role of cannabinoids, particularly of Cannabinoid-2 agonists devoid of psychotropic side effects, in glioma therapy could have a foundation in glioblastomas, because they were all positive, though weakly, to Cannabinoid-2.

11 The presence of neurotrophins and their receptors, mainly NT3 and TrkC, implies a possible role of these pathways in glioma growth/invasion, however, further investigations are required to verify this hypothesis and a potential relationship between cannabinoids and neurotrophins.





12 Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas -- possible role of marijuana inhalation. Foroughi et-al 2011. Child's Nervous System 27- 671-679.

12 Case report We report two children with CANCER - septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision,leaving behind a small residual in each case.

12 During Magnetic Resonance Imaging (MRI) surveillance in the first three years,
one case was dormant and the other demonstrated slight improvement in size, followed by clear regression of both residual tumors over the following three-year period. Neither patient received any conventional adjuvant treatment. The tumors regressed over the same period of time that marijuana was consumed via inhalation, raising the possibility that the marijuana played a role in the tumor regression.


12 Conclusion We advise caution against instituting adjuvant therapy or further aggressive surgery for small residual PAs, especially in eloquent locations, even if there appears to be slight progression, since regression may occur later. Further research may be appropriate to elucidate the increasingly
recognized effect of marijuana/phyto cannabinoids on gliomas (brain tumor).




13 d9-THC inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Caffarel et-al 2006. Cancer Research 66- 6615-6621.

13 Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer

13 It was proposed that phytocannabinoids are involved in the control of cell fate. Thus, these compounds can modulate proliferation, differentiation (stem cell yields different cell types), and survival in different manners depending on the cell type and its physiopathological context. However, little is known about the effect of phytocannabinoids on the cell cycle, the main process controlling cell fate. Here, we show that d9-THC -

13 THC, through activation of Cannabinoid-2 receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis (programmed cell death). In particular, d9-THC arrests cells in G2-M via down-regulation of Cdc2, as implied by the lowered sensitivity to d9-THC acquired by Cdc2-overexpressing cells.

13 Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by d9-THC. We likewise analyzed by real-time quantitative PCR the expression of Cannabinoid-1  and Cannabinoid-2 cannabinoid receptors in a series of human breast tumor and nontumor samples. We found a correlation between Cannabinoid-2 expression and histologic grade of the tumors. There was likewise an association between Cannabinoid-2 expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant Cannabinoid-2 expression was detected in nontumor breast tissue.




14 Anti-tumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. Di Marzo et-al 2006. Journ. of Pharmacology & Experimental Therapeutics Fast Forward 318- 1375-1387.

14 Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.

14 d9-THC exhibits anti-tumor effects on various cancer cell types, however, its use in chemotherapy is limited by its psychotropic activity. We investigated the anti-tumor activities of other plant cannabinoids, i.e. cannabidiol, cannabigerol, cannabichromene, cannabidiol-acid and THC-acid, and assessed whether there is any advantage in using marijuana extracts over pure cannabinoids. Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth , with significantly lower potency in noncancer cells.

14 The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by subcutaneous injection into athymic rodents of human breast carcinoma (cancer) or rat v-K-ras-transformed thyroid epithelial cells, and reduced lung metastases deriving from intra-paw injection of cells.

14 Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis (programmed cell death) via: 1) direct or indirect activation of cannabinoid CB2 and vanilloid TRPV1 receptors; and 2) cannabinoid/vanilloid receptor-independent elevation of intracellular Ca2+ and reactive oxygen species.




15 The endogenous cannabinoid anandamide (neurotransmitter) inhibits human breast cancer cell proliferation. De Petrocellis et-al 1998.  Proceedings of the National Academy of Sciences of the United States of America 95- 8375-8380.

15 Anandamide was the first brain metabolite shown to act as a ligand of ‘‘central’’ CB-1 cannabinoid
receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 mM and 83–92% maximal constraint at 5–10 mM.

15 The proliferation of several other non mammary tumoral cell lines was not affected by 10 mM anandamide (neurotransmitter). The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells however, was accompanied by a reduction of cells in the S phase of the cell cycle. A stable analogue of anandamide (R)-methanandamide, another endogenous cannabinoid, 2-arachidonoylglycerol, and the synthetic cannabinoid HU-210 likewise inhibited EFM-19 cell proliferation,whereas arachidonic acid was much less effective.

15 These cannabimimetic substances displaced the binding of the selective cannabinoid agonist [3H]CP 55,940 to EFM-19 membranes with an order of potency identical to that observed for
the constraint of EFM-19 cell proliferation. Moreover, anandamide cytostatic effect was inhibited by the selective CB-1 receptor antagonist SR141716A. Cell proliferation was arrested by a prolactin mAb and enhanced by exogenous human prolactin, whose mitogenic action was reverted by very low (0.1–0.5 mM) doses of anandamide.

15 Anandamide suppressed the levels of the long form of the prolactin receptor in both EFM-19 and MCF-7 cells, as well as a typical prolactin induced response, i.e., the expression of the breast cancer cell susceptibility gene brca1. These data imply that anandamide blocks human breast cancer cell proliferation through CB-1- like receptor-mediated constraint of endogenous prolactin
action at the level of prolactin receptor.




Illustration Above - Endocannabinoids in the body- When imbalanced, Cancer can result.





16 Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.McAllister et-al 2007. Molecular Cancer Therapeutics 6- 2921-2927.

16 Here, we report that cannabidiol (CBD), a phytocannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion.

16 These effects seemed to occur as the result of a constraint of the Id1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness.




17 Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition.Cafferal et-al 2010.  Molecular Cancer 9- 196.

17 Taken together, these results provide a strong preclinical information for the use of phytocannabinoid-based therapies for the management of ErbB2-positive breast cancer.

17 Our results show that both d9-THC, the most abundant and potent phyto cannabinoid in cannabis, and JWH-133, a non-psychotropic Cannabinoid-2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu rodents. Histological analyses of the tumors revealed that phyto cannabinoids inhibit cancer cell proliferation,activate cancer cell apoptosis, and impair tumor angiogenesis (formation of new blood cells). Cannabinoid antitumoral action relies, at least partially, on the constraint of the pro-tumorigenic Akt pathway. We likewise found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB-2.



18 Cannabinoid receptors as a novel target for the treatment of prostate cancer. Sarfaraz et-al 2005.  Cancer Research 65- 1635-1641.

18 Recently, phytocannabinoids have received considerable attention due to their diverse pharmacological activities such as cell growth constraint, anti-inflammatory effects, and tumor regression. Our results imply that treatment of androgen (male characteristics)-responsive human prostate carcinoma (cancer) LNCaP cells resulted in a decrease in intracellular and secreted levels of Prostate-Specific Antigen - PSA, with concomitant constraint of androgen receptor, cell growth, and induction of apoptosis (programmed cell death).

18 We conclude that phytocannabinoids should be considered as agents for the management of prostate cancer. If our hypothesis is supported by in vivo experiments, then the long-term implications of our work could be to develop non–habit-forming cannabinoid agonist(s) for the management of prostate cancer.




19 Anti-proliferative & apoptotic effects of anandamide (neurotransmitter) in human prostatic cancer cell lines.Mimeault et-al 2003. , Prostate 56- 1-12.

19 The potent anti-proliferative and cytotoxic effects of ANA on metastatic prostatic cancer cells might provide foundation for the design of new therapeutic agents for effective treatment of recurrent and invasive prostatic cancers.

19 ANA activated a decrease of EGFR levels on LNCaP, DU145, and PC3 prostatic cancer cells by acting through cannabinoid CB(1) receptor subtype and this led to a constraint of the EGF-stimulated growth of these cells. Moreover, the G(1) arrest of metastatic DU145 and PC3 growth was accompanied by a massive cell death by apoptosis (programmed cell death) and/or necrosis while LNCaP cells were less sensitive to cytotoxic effects of ANA.

19 The apoptotic/necrotic responses activated by ANA on these prostatic cancer cells were likewise potentiated by the acidic ceramidase inhibitor, N-oleoylethanolamine and partially inhibited by the specific ceramide synthase inhibitor, fumonisin B1 indicating that these cytotoxic actions of ANA might be activated via the cellular ceramide production.



20 d9-THC activates apoptosis (programmed cell death) in human prostate PC-3 cells via a receptor-independent mechanism. Ruiz et-al 1999.  FEBS Letters 458- 400-404.

20 The effect of d9-THC - Tetrahydrocannabinol, the main psycho-active ingredient of cannabis, in human prostate cancer cells PC-3 was investigated. d9-THC caused apoptosis (programmed cell death) in a dose-dependent manner. Morphological and biochemical changes activated by d9-THC in prostate PC-3 cells shared the characteristics of an apoptotic phenomenon.

20 First, loss of plasma membrane asymmetry determined by fluorescent annexin V binding. Second, presence of apoptotic bodies and nuclear fragmentation observed by DNA staining with 4′,6-diamino-2-phenylindole (DAPI). Third, presence of typical ‘ladder-patterned’ DNA fragmentation. Central cannabinoid receptor expression was observed in PC-3 cells by immunofluorescence studies.

20 However, several results indicated that the apoptotic effect was cannabinoid receptor-independent, such as lack of an effect of the potent cannabinoid agonist WIN 55,212-2, inability of cannabinoid antagonist AM 251 to prevent cellular death caused by d9-THC and absence of an effect of pertussis toxin pretreatment.




21 The role of cannabinoids in prostate cancer- Basic science perspective & potential clinical applications. Ramos & Bianco. 2012. Journ. of Urology 28- 9-14.

21 It is our conclusion that it would be of interest to conduct clinical trials involving medicinal marijuana or other cannabinoid agonists, comparing clinical markers such as Prostate-Specific Antigen - PSA with controls, especially in men with bone metastatic prostate cancer, whom would not only benefit from the possible anti-androgenic (male characteristics) effects of cannabinoids and likewise from analgesia of bone pain, improving quality of life, while reducing narcotic consumption and preventing opioid dependence.

21 Cannabis Sativa L. and its main active ingredient d9-THC have long been used for numerous purposes throughout history including medicinal, textile, and recreational. Since its legal banning in the United States in 1937, it has become an issue of taboo and controversy, frowned upon for its recreational uses and psychotropic effects.

21 Nonetheless, the endocannabinoid signaling system has recently been the focus of medical research and considered a potential therapeutic target since the late 1980s when Howlett and colleagues identified and characterized the distinct cannabinoid receptor in rat brain. The antagonizing effect of cannabinoids in the male reproductive system and physiology can be dated to 1974 where experimental models in male rats demonstrated depression of spermatogenesis and decrease in circulating testosterone levels.

21 Sarfaraz and colleagues demonstrated a dialed-up expression of both Cannabinoid-1  and Cannabinoid-2 receptors in cultured prostate cancer cells when compared with normal prostate cells, treatment of prostate cancer cells with cannabinoid Cannabinoid-1 /Cannabinoid-2 agonist WIN-55,212-2 (synthetic experimental cannabinoid) results in a dose and time dependent decrease in cell viability ,and dialed-up apoptosis (programmed cell death) along with decrease in androgen (male characteristics) receptor protein expression, Prostate-Specific Antigen - PSA expression, and secreted PSA, implying that cannabinoids should be considered as agents for the management of prostate cancer. If the hypothesis is supported by in vivo experiments.




22 Non-d9 THC cannabinoids inhibit prostate carcinoma (cancer) growth in vitro & in vivo- pro-apoptotic effects & underlying mechanisms. De Petrocellis et-al 2013.  British Journ. of Pharmacology 168- 79-102.

22 In conclusion, the in vitro data presented here allow us to imply that non-THC cannabinoids, and CBD in particular, retard proliferation and cause apoptosis (programmed cell death) of PCC via a combination of cannabinoid receptor-independent, cellular and molecular mechanisms. Our data, however, do not argue against the previously implied role of Cannabinoid-1  and Cannabinoid-2 receptors in prostate carcinoma (cancer), although they do exclude the participation of these receptors in the effects of non-THC cannabinoids.

22 Indeed, the effects reported here, together with previously reported cannabinoid receptor-mediated effects of d9-THC on PCCs, might encourage clinical studies on cannabinoids and marijuana extracts as a therapy for human prostate carcinoma (cancer), either as single agent or in combination with existing compounds. Our supplementary observation that differentiation (stem cell yields different cell types) of an ‘androgen (male characteristics)-dependent’ cell into a more malignant and ‘androgen-unresponsive’ phenotype dial-up its sensitivity to the pro-apoptotic effect of CBD might provide a new strategy to deal with the frequent loss of efficacy of AR antagonists against prostate carcinoma (cancer) growth seen after only a few years of treatment.




23 The endogenous cannabinoid, anandamide (neurotransmitter), activates cell death in colorectal carcinoma (cancer) cells- a possible role for cyclooxygenase-2.Pastos et-al 2005.  Gut 54- 1741-1750.

23 These findings imply anandamide may be a useful chemopreventive/therapeutic agent for colorectal cancer as it targets cells that are high expressors of COX-2, and may likewise be used in the eradication of tumour cells that have become resistant to apoptosis (programmed cell death).

23 Anandamide inhibited the growth of CRC (colon cancer cell) lines HT29 and HCA7/C29 ....moderate and high COX-2 (Prostaglandin enzyme) expressors, respectively) however, had little effect on the very low COX-2 (Prostaglandin enzyme) expressing CRC (colon cancer cell)  line, SW480. Induction of cell death in HT29 and HCA7/C29 cell lines was partially rescued by the COX-2 (Prostaglandin enzyme) selective inhibitor NS398.

23 Cell death activated by anandamide (neurotransmitter) was neither apoptosis (programmed cell death) nor necrosis. Moreover, constraint of fatty acid amide hydrolase potentiated the non-apoptotic cell death, indicating that anandamide (neurotransmitter) activated cell death was mediated via metabolism of anandamide (neurotransmitter) by COX-2, rather than its degradation into arachidonic acid and ethanolamine. Interestingly, both PGE2-EA and PGD2-EA activated classical apoptosis (programmed cell death).



24 Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. Aviello et-al 2012. Journ. of Molecular Medicine  Di Marzo et-al 2006. op-cit

24 Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis Sativa L., exerts pharmacological actions (antioxidant and intestinal anti inflammatory) and mechanisms (constraint of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. Thus, we investigated its possible chemopreventive effect in the model of colon cancer activated by azoxymethane (AOM) in rodents.

24 Azoxymethane-AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 (Prostaglandin enzyme) (Prostaglandin enzyme)and down-regulation of caspase-3. Cannabidiol-reduced ACF, polyps and tumours and counteracted Azoxymethane-AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma (cancer) cell lines, cannabidiol protected DNA from oxidative damage, dial-upd endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.




25 Inhibition of skin tumor growth & angiogenesis (formation of new blood cells) in vivo by activation of cannabinoid receptors. Casanova et-al 2003. Journ. of Clinical Investigation 111- 43-50.

25 Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas (brain tumor) and the wide tissue distribution of the two subtypes of cannabinoid receptors (Cannabinoid-1  and Cannabinoid-2), we studied the potential utility of these compounds in anti–skin tumor therapy. Here we show that the Cannabinoid-1  and the Cannabinoid-2 receptor are expressed in normal skin and skin tumors of rodents and humans.

25 In cell culture experiments pharmacological activation of cannabinoid receptors activated the apoptotic death of tumorigenic epidermal cells, whereas the viability of non transformed epidermal cells remained unaffected. Local dosing of the mixed Cannabinoid-1 /Cannabinoid-2 agonist WIN-55,212-2 (synthetic experimental cannabinoid) or the selective Cannabinoid-2 agonist JWH-133 activated a considerable growth constraint of malignant tumors generated by inoculation of epidermal tumor cells into nude rodents.

25 Cannabinoid-treated tumors demonstrated a dialed-up number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and lowered expression of proangiogenic factors (VEGF (blood vessel growth factor), placental growth factor, and angiopoietin 2).

25 Abrogation of EGF-R function was likewise observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.




26 Cannabis-induced cytotoxicity in leukemic (bone marrow - white blood cancer) cell lines. Powles et-al 2005.  Blood 105- 1214-1221

26 d9-TRC is the active metabolite of marijuana. d9-THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (Cannabinoid-1 -R and Cannabinoid-2-R) play in this process is less clear. We therefore investigated the role of the CB-Rs in mediating apoptosis (programmed cell death) in 3 leukemic (bone marrow - white blood cancer) cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death.  

26 We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective Cannabinoid-1-R and Cannabinoid-2-R antagonists and agonists to determine their individual roles in this process. We have shown that d9-THC is a potent activator of apoptosis (programmed cell death), even at 1 × IC50 concentrations and as early as 6 hours after exposure to the drug.

26 These effects were seen in leukemic (bone marrow - white blood cancer) cell lines as well as in peripheral blood mononuclear cells. Additionally, d9-THC did not appear to act synergistically with cytotoxic agents such as cisplatin. One of the most intriguing findings was that d9-THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways. Both apoptosis (programmed cell death) and gene expression changes were altered independent of p53 and the CB-Rs.




27 d9-THC-induced apoptosis (programmed cell death) in Jurkat (immortal human lymph cells) leukemic (bone marrow - white blood cancer) T cells is regulated by translocation of Bad to mitochondria. Jia 2006. Molecular Cancer Research 4- 549-562.

27 Plant-derived cannabinoids, including d9-THC - Tetrahydrocannabinol, activate apoptosis (programmed cell death) in leukemic (bone marrow - white blood cancer) cells, although the precise mechanism remains unclear. In the current study, we investigated the effect of d9-THC on the upstream and downstream events that modulate the extracellular signal-regulated kinase (ERK) module of mitogen-activated protein kinase pathways primarily in human Jurkat (immortal human lymph cells) leukemia T cells.

27 The data demonstrated that d9-THC down-regulated Raf-1/mitogen-activated protein kinase/ERK kinase (MEK)/ERK/RSK pathway leading to translocation of Bad to mitochondria. d9-THC likewise lowered the phosphorylation of Akt. However, no significant association of Bad translocation with phosphatidylinositol 3-kinase/Akt and protein kinase A signaling pathways was noted when treated cells were examined in relation to phosphorylation status of Bad by Western blot and localization of Bad to mitochondria by confocal analysis.

27 Moreover, d9-THC treatment lowered the Bad phosphorylation at Ser112 however, failed to alter the level of phospho-Bad on site Ser 136 that was reported to be associated with phosphatidylinositol 3-kinase/Akt signal pathway. Jurkat (immortal human lymph cells) cells expressing a constitutively active MEK construct were found to be resistant to d9-THC-mediated apoptosis (programmed cell death) and failed to exhibit lowered phospho-Bad on Ser112 as well as Bad translocation to mitochondria.

27 Finally, use of Bad small interfering RNA reduced the expression of Bad in Jurkat (immortal human lymph cells) cells leading to dialed-up resistance to d9-THC-mediated apoptosis (programmed cell death). Together, these data implied that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in d9-THC-induced apoptosis (programmed cell death) in Jurkat cells.




28 Enhancing the in vitro cytotoxic activity of D9-THC in leukemic (bone marrow - white blood cancer) cells through a combinatorial approach. Liu et-al 2008.  Leukemia & Lymphoma 49- 1800-1809.

28 Overall, these results demonstrate for the first time that a combination approach with THC and established cytotoxic agents may enhance cell death in vitro. Additionally the MAPK/ERK pathway appears responsible in part for these effects.

28 d9 THC is the active metabolite of marijuana, which has demonstrable cytotoxic activity in vitro. In support of our previously published data, we have investigated the interactions between THC and anti-leukemia therapies and studied the role of the signalling pathways in mediating these effects. Results demonstrated clear synergistic interactions between THC and the cytotoxic agents in leukemic (bone marrow - white blood cancer) cells.

28 Additionally, exposure of cells to sublethal levels of THC (1 microM) sensitised cells to these cytotoxic agents, by reducing IC(50) values by approximately 50%. Sensitisation appeared to be dependent upon the ability of THC to down regulate phosphorylated ERK, as cells dominantly expressive of MEK were not sensitised to the cytotoxic drugs by equimolar amounts of THC.




29 Enhancing the activity of cannabidiol & other cannabinoids in vitro through modifications-drug combinations & treatment schedules Scott et-al 2013.  33- 4373-4380.

29 Cannabinoids are the bioactive ingredients of the marijuana plant that display a diverse range of therapeutic qualities. We explored the activity of six cannabinoids, used both alone and in combination in leukaemic cells. Cannabinoids were cytostatic and caused a simultaneous arrest at all phases of the cell cycle. Re-culturing pre-treated cells in drug-free medium resulted in dramatic reductions in cell viability.

29 Moreover, combining cannabinoids was not antagonistic. We imply that the activities of some cannabinoids are influenced by treatment schedules; therefore, it is important to carefully select the most appropriate strategy in order to maximise their efficacy




30 Dronabinol has preferential anti leukemic (bone marrow - white blood cancer) activity in acute lymphoblastic & myeloid leukemia with lymphoid differentiation (stem cell yields different cell types) patterns. BMC Cancer. Kampa-Schittenhelm et-al 2016.

30 Our study provides rigorous data to support clinical evaluation of d9-THC as a low-toxic therapy option in a well defined subset of acute leukemia patients.

30 Meaningful antiproliferative as well as proapoptotic effects were demonstrated in a subset of cases – with a preference of leukemia cells from the lymphatic lineage or acute myeloid leukemia cells expressing lymphatic markers. Induction of apoptosis (programmed cell death) was mediated via Cannabinoid-1 receptor as well as Cannabinoid-2, and expression of CB receptors was a prerequisite for therapy response in our models. Importantly, we demonstrate that anti leukemic (bone marrow - white blood cancer) concentrations are achievable in vivo.




Labels: cancer gliomas Cannabinoid Apoptosis tumor regression

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