CANCER - 20 MARIJUANA RESEARCH REPORTS 2000-2017
Researchers - No question that cannabis CBD and THC kills cancer
"Twenty handpicked clinical trials and research studies that cannabinoids, THC and CBD kill cancer cells in animals and humans, supporting thousands of patient claims that high doses of cannabis oil kills cancer."
1 Phyto-cannabinoids: potential anticancer agents Manuel Guzman. 2003. Nature Reviews Cancer 3: 745-755.
1 Could phyto-cannabinoids be used to develop new anti-cancer therapies?
1 Phyto-cannabinoids - the active components of C. Sativa and their derivatives exert
major positive effects in cancer patients by: preventing nausea, vomiting and chronic pain while stimulating appetite. In addition, cannabinoids such as THC and CBD have been shown to inhibit the growth of tumour cells in culture and mammal models by modulating key cell-signalling pathways. phyto-cannabinoids are usually well tolerated, and do not yield the generalized toxic effects of conventional chemotherapies.
1 Tumours that are sensitive to cannabinoid-induced growth inhibition:
Tumour type - Lung carcinoma (epithelial cancer) in-vivo (rodent); Reduced tumour size; in vitro cell-growth inhibition
glioma (brain tumor) in-vivo (rodent, rat); Reduced tumour size; Cannabinoid-1, Cannabinoid-2 receptor in vitro programmed cell death - programmed cell death - apoptosis
Thyroid epithelioma in-vivo (rodent); Reduced tumour size; Cannabinoid-1 receptor
in vitro cell-cycle termination
Lymphoma/leukaemia in-vivo (rodent); Reduced tumour size; Cannabinoid-2 receptor
in vitro programmed cell death - programmed cell death - apoptosis
Skin carcinoma (epithelial cancer) in-vivo (rodent); Reduced tumour size; Cannabinoid-1, Cannabinoid-2 receptor
in vitro programmed cell death - programmed cell death - apoptosis
Uterus carcinoma (epithelial cancer) In vitro Cell-growth inhibition.
Breast carcinoma (epithelial cancer) In vitro Cell-cycle termination Cannabinoid-1
Prostate carcinoma (epithelial cancer) In vitro programmed cell death - programmed cell death - apoptosis Cannabinoid-1
Neuroblastoma In vitro programmed cell death - programmed cell death - apoptosis
2 Cannabidiol enhances the inhibitory effects of d9 THC on human glioblastoma (brain cancer) cell proliferation & survival. Marcu et-al 2010. Molecular Cancer Therapeutics 9: 180-189. Guzman. 2003 op. cit.
2 The cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonist d(9)-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in-vivo, and is currently being used in a clinical trial for the therapy of glioblastoma (brain cancer). It has been suggested that other plant-derived phyto-cannabinoids, which do not interact efficiently with Cannabinoid-1 and Cannabinoid-2 receptors, can modulate the actions of d(9)-THC. There are conflicting reports, Even so, as to what extent other phyto-cannabinoids can modulate d(9)-THC action, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of d(9)-THC.
2 We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with d(9)-THC. In the U-251 and SF126 glioblastoma (brain cancer) cell lines, d(9)-THC and CBD acted synergistically to inhibit cell proliferation.
2 The therapy of glioblastoma (brain cancer) cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and programmed cell death - programmed cell death - apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination therapy was unique. Our results suggest that the addition of cannabidiol-CBD to d(9)-THC may improve the overall effectiveness of d(9)-THC in the treatment of glioblastoma in cancer patients.
3 d9THC inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth & metastasis in-vivo. Preet et-al 2008. Oncogene 10: 339-346.
3 d9-Tetrahydrocannabinol (THC) is the main cannabinoid of cannabis 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 action of phyto-cannabinoids like d9THC on epidermal growth factor receptor-overexpressing lung cancers, which are often profoundly aggressive and resistant to Chemo.. In this study, we characterized the effects of d9THC on the Epidermal growth factor-induced growth and metastasis of human non-small cell lung cancer using the cell lines A-549 (human tumors) and SW-1573 (human tumors)as in vitro models.
3 We found that these cells express the cannabinoid receptors Cannabinoid-1 and Cannabinoid-2, known targets for d9THC action, and that d9THC inhibited Epidermal growth factor-induced growth, chemotaxis and chemo invasion. Moreover, signaling investigations indicated that d9THC may act by inhibiting the Epidermal growth factor-induced phosphorylation of ERK1/2, JNK1/2 and AKT. d9THC also induced the phosphorylation of focal adhesion kinase at tyrosine-97.
3 In addition, in in-vivo investigations in severe combined immunodeficient mice, there was a significant inhibition of the subcutaneous tumor growth and lung metastasis of A-549 (human tumors) cells in d9THC-treated mammals as compared to vehicle-treated controls. Tumor samples from d9THC-treated mammals revealed antiproliferative and antiangiogenic effects of d9THC. Our study suggests that phyto-cannabinoids like d9THC should be explored as new therapeutic molecules in controlling the growth and metastasis of certain lung cancers.
In addition to phyto-cannabinoids' ability to moderate glioma (brain tumor) cells, separate preclinical investigations demonstrate that phyto-cannabinoids and endocannabinoids can also inhibit the proliferation of other various cancer cell lines, including breast carcinoma (epithelial cancer), prostate carcinoma, colorectal carcinoma, gastric adenocarcinoma, skin carcinoma,leukemia cells, neuroblastoma,lung carcinoma, uterus carcinoma (epithelial cancer), thyroid epithelioma, pancreatic adenocarcinoma, cervical carcinoma,] oral cancer, biliary tract cancer (cholangiocarcinoma (epithelial cancer)) and lymphoma,among others. In some instances, improved anti-cancer action has been reported when phyto-cannabinoids are administered in concert with one another, rather than in isolation.
4a Phyto-cannabinoids induce programmed cell death - programmed cell death - apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Carracedo et-al 2006. Cancer Research 66: 6748-6755.
4a d9-tetrahydrocannabinol–induced programmed cell death - programmed cell death - apoptosis.Phyto-cannabinoids also reduced the growth of tumor cells in two mammal models of pancreatic cancer. In addition, cannabinoid therapy inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased programmed cell death - programmed cell death - apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, the results presented here show that phytocannabinoids lead to programmed cell death - programmed cell death - apoptosis of pancreatic tumor cells via a Cannabinoid-2 receptor and de novo synthesized ceramide (signaling molecule)-dependent up-regulation of p8 and the endoplasmic reticulum stress–related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the therapy of pancreatic cancer.
4a Illustrations: Cannabinoid receptor immunostaining in human pancreatic cancer tissues. Low (a, g), moderate (b, h) and strong (c, i) immunostaining for Cannabinoid-1 or Cannabinoid-2 receptors in pancreatic cancer cells.
5 Cannabinoids in pancreatic cancer: correlation with survival & chronic pain. Michalski et-al 2008. International Journal of Cancer 122: 742-750.
5 Most recently, stress-regulated protein p8 has been identified as a downstream target of the proapoptotic sphingolipid ceramide (signaling molecule), serving as an essential mediator of growth inhibitory properties of phyto-cannabinoids by upregulating endoplasmic reticulum stress-related genes. Importantly, some of these effects are communicated by the endocannabinoid system in vitro, and inhibition of endocannabinoid inactivation has revealed tumor growth inhibition comparable to that observed with exogenously administered phyto-cannabinoids. Even so,phyto-cannabinoids in some cases also exert growth-fostering activities through growth factor/receptor systems or by suppression of an anti-tumor immune system reaction.
5 Altogether, antiproliferative effects seem to prevail, and therefore phyto-cannabinoids are considered potential candidate drugs in anti-tumor therapies, simultaneously alleviating cancer-related chronic pain and cachexia. In line with a variety of in vitro investigations and mammal experiments, a recent study showed some response of malignant glioma (brain tumors) to intratumoral cannabinoid infusions in humans, underlining a potential prospect for their in-vivo use.
5 Here, we concomitantly analyze the expression of cannabinoid receptors and endocannabinoid metabolizing enzymes. Our results demonstrate a correlation between longer survival in pancreatic cancer patients, and low Cannabinoid-1 receptor levels or high FAAH as well as MGLL levels in tissue specimens.
6 Inhibition of cancer cell invasion by phyto-cannabinoids via increased cell expression of tissue inhibitor of matrix metalloproteinases-1. Ramer & Hinz. 2008. Journal of the National Cancer Institute 100: 59-69.
6 Cervical cancer remains a global health related issue among females of Sub-Saharan Africa, with over half a million new cases reported each year. Different therapeutic regimens have been suggested in various regions of Africa, Even so, over a quarter of a million women die of cervical cancer, annually. This makes it the most lethal cancer amongst black women and calls for urgent therapeutic strategies. In this study, we compare the anti-proliferative effects of raw concentrate of C. Sativa and its main compound cannabidiol on different cervical cancer cell lines.
6 Protocol - To achieve our aim, phytochemical screening, assess cell metabolic action MTT analysis, cell growth analysis, flow cytometry, morphology analysis, Western blot, caspase 3/7 analysis, and Adenotriphosphate - ATP measurement analysis was conducted.
6 Results - Results obtained indicate that both cannabidiol and C. Sativa extracts were able to halt cell proliferation in all cell lines at varying concentrations. They further revealed that programmed cell death - apoptosis was induced by cannabidiol as shown by increased sub G0/G1 and programmed cell death - apoptosis through annexin V. programmed cell death - apoptosis was confirmed by overexpression of p53, caspase 3 and bax. programmed cell death - apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a reduction in the Adenotriphosphate - ATP levels.
6 Conclusions- data suggest that cannabidiol rather than C. Sativa raw concentrates prevent cell growth and induce cell death in cervical cancer cell lines.
7 Phyto-cannabinoids inhibit cellular respiration of human oral cancer cells. Whyte et-al 2010. Pharmacology 85: 328-335.
7 Preamble and purpose- The main phyto-cannabinoids,d(9)-THC and d(8)-tetrahydrocannabinol (d(8)-THC) are known to disrupt the mitochondria-organelles and tumors. Observations prompted the investigation phytocannabinoid effects on the mitochondria-organelles oxygen burning in human oral cancer cells - T-u-183. This epithelial cell lines demonstrated an overexpression of b-c-l-2 gene cancer regulator) which is very resistant to ALK - anti-cancer drugs.
7 EXPERIMENT - An analyzer that measures the oxygen concentration in cellular or mitochondrial-organelles suspensions was used. RESULT- A quick decline in the respiration rate was observed when d(9)-THC or d(8)-THC was added to the cells. The inhibition of respiration was concentration-dependent, and d(9)-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was found to be ineffective; suggesting the effects of d(9)-THC and d(8)-THC were not related to the cannabinoid receptors. Inhibition of oxygen consumption by cyanide confirmed that the oxidations occurred somewhere in the mitochondria-organelles respiratory chain. d(9)-THC was shown to inhibit the respiration of isolated mitochondria-organelles from cattle hearts.
7 IMPLICATIONS - CONCLUSIONS - These results definitively show that cannabinoids are anti cancer - are potent inhibitors of Tu 183 cellular respiration and are toxic to this profoundly malignant tumor.
8 The dual effects of d(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion action at low concentration & programmed cell death - apoptosis induction at high concentration. Leelawat et-al 2010. Cancer Investigation 28: 357-363.
8 Currently, only Gemcitabine, a Chemo. medication, plus platinum demonstrates the considerable action for cholangiocarcinoma. The anti-cancer effect of d (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers.
8 We therefore appraise anti-tumor effects of d9THC on cholangiocarcinoma cells. Both cholangiocarcinoma cell lines and surgical specimens from cholangiocarcinoma patients expressed cannabinoid receptors. d9THC inhibited cell proliferation, migration and invasion, and induced cell programmed cell death - apoptosis. d9THC also reduced actin polymerization and reduced tumor cell survival in anoikis analysis. pMEK1/2 and pAkt demonstrated the lower extent than untreated cells. Consequently, d9THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.
9 Cannabinoid receptor-mediated programmed cell death - apoptosis induced by R(+)-methanandamide (an endocannabinoid) & Win55,212 (synthetic cannabinoid) is associated with ceramide (signaling molecule) accumulation & p38 activation in mantle cell lymphoma. Gustafsson et-al 2006. Molecular Pharmacology 70: 1612-1620.
9 We have recently shown that cannabinoids induce growth inhibition and programmed cell death - apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (Cannabinoid-1 and Cannabinoid-2). In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated. Induction of programmed cell death - apoptosis after therapy with the synthetic agonists.
9 In summary, these results suggest that concurrent ligation of Cannabinoid-1 and Cannabinoid-2 with either R(+)-MA or Win55 (synthetic cannabinoid) induces programmed cell death - apoptosis via a sequence of events in Mantle cell non-Hodgkin's lymphoma cells: accumulation of ceramide (signaling molecule), phosphorylation of p38, depolarization of the mitochondria-organelles membrane, and caspase activation. Although induction of programmed cell death - apoptosis was observed in both Mantle cell non-Hodgkin's lymphoma cell lines and main MCL, normal B cells remained unaffected. The present data suggest that targeting Cannabinoid-1/Cannabinoid-2 may have therapeutic potential for the therapy of mantle cell lymphoma.
10 Expression of cannabinoid receptors type 1 & type 2 in non-Hodgkin lymphoma: Growth inhibition by receptor activation. Gustafsson et-al 2008. International Journal of Cancer 123: 1025-1033.
10 endogenous (made by the body) and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL). In this study, we appraised the expression of cannabinoid receptors type 1 and type 2 (Cannabinoid-1 and Cannabinoid-2) in non-Hodgkin lymphomas of B cell type.
10 A majority of the lymphomas expressed higher mRNA levels of Cannabinoid-1 and/or Cannabinoid-2 receptor as compared to reactive lymphoid tissue. With the exception of Mantle cell non-Hodgkin's lymphoma, which uniformly overexpressed both Cannabinoid-1 and Cannabinoid-2, the levels of cannabinoid receptors within other lymphoma entities were profoundly variable, ranging from 0.1 to more than two hundred times the expression in reactive lymph nodes.
10 Low levels of the splice variant Cannabinoid-1a, previously shown to have a different affinity for cannabinoids than Cannabinoid-1, were found in forty four percent of the lymphomas, while Cannabinoid-1b expression was not found. In functional investigations using Mantle cell non-Hodgkin's lymphoma,
10 Burkitt lymphoma (BL), chronic lymphocytic leukemia (CLL) and plasma cell leukemia cell lines, the stable anandamide (an endocannabinoid) analog R(+)-methanandamide (R(+)-MA) induced cell death only in Mantle cell non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL) cells, which overexpressed both cannabinoid receptors, but not in BL. in-vivo therapy with R(+)-MA caused a significant reduction of tumor size and mitotic index in mice xenografted with human Mantle cell non-Hodgkin's lymphoma. Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing Cannabinoid-1 and Cannabinoid-2.
11 Marijuana extract therapy for terminal acute lymphoblastic leukemia. Singh & Bali. 2013. Case Reports in Oncology 6: 585-592.
11 There has been an profusion of research possessing the cytotoxic (toxic to cells) effects of cannabinoids on leukemic cell lines in the form of in vitro and in-vivo investigations . An oncology and hematology journal, Blood, has published many papers over the years constructing the biochemical pathway to be elicited by the anti-cancer properties of cannabinoids. Our goal, upon examination of this significant case study, which demonstrated complete disease control and a dose response curve, is to invest effort in and to focus on research and development to advance this therapy.
11 An emphasis needs to be placed on determining the correct cannabinoid ratios for different types of cancer, the best method of administration, quality control and standardization of the marijuana strains and their growing conditions as well as therapeutic dosing ranges for various cancers contingent on staging and ages. Toxicity profiles favor therapies deriving from marijuana because toxicity within the body is greatly reduced and the devastating side effects of Chemo can be eliminated. It is unfortunate that this therapy does come with some unwanted psychosomatic properties;
11 Even so, these might be eliminated by target therapies of non psychoactive cannabinoids such as cannabidiol which has garnered much attention as being a potent anti-inflammatory and possible antileukemic and anticancer agent. It is acknowledged that significant research needs to be conducted to reproduce these results and that in vitro investigations cannot always be reproduced in clinical trials and the human physiological microenvironment.
11 Even so, the many research investigations and this particular clinical case are powerful enough to warrant implementing clinical trials to determine dose ranges, cannabinoid profiles and ratios, the protocol of administration that produce the most efficacious therapeutic responses and the reproducibility of the results. It is tempting to speculate that, with the integration of this care in a setting of full medical and laboratory support, a better outcome may indeed be achieved in the future.
12 Study finds no cancer-cannabis connection. Washington Post. May 26, 2006.
12 The largest study of its kind has unexpectedly concluded that smoking cannabis, even regularly and heavily, does not lead to lung cancer.
12 Tashkin study, funded by the National Institutes of Health's National Institute on Drug Abuse, involved 1,200 people in Los Angeles who had lung, neck or head cancer and an additional 1,040 people without cancer matched by age, sex and neighborhood.
12 They were all asked about their lifetime use of cannabis, tobacco and alcohol. The heaviest cannabis smokers had lighted up more than twenty two thousand times, while moderately heavy usage was defined as smoking eleven to twenty two thousand cannabis cigarettes. Tashkin found that even the very heavy cannabis smokers showed no increased incidence of the three cancers studied.
12 "This is the largest case-control study ever done, and everyone had to fill out a very extensive questionnaire about cannabis use," he said. "Bias can creep into any research, but we controlled for as many confounding factors as we could, and so I believe these results have real meaning."
12 The new findings "were against our expectations," said Donald Tashkin of the University of California at Los Angeles, a pulmonologist who has studied cannabis for thirty years.
"We hypothesized that there would be a positive association between cannabis use and lung cancer, and that the association would be more positive with heavier use," he said. "What we found instead was no association at all, and even a suggestion of some preservation effect."
12 Federal health and drug enforcement officials have widely used Tashkin previous work on cannabis to make the case that the drug is dangerous. Tashkin said that while he still believes cannabis is potentially harmful, its cancer-causing effects appear to be of less concern than previously thought.
13 A population-based case-control study of cannabis use & head & neck squamous cell carcinoma. Liang et-al 2009. Cancer Prevention Research 2: 759-768.
13 Cannabinoids, constituents of cannabis vapor, have been recognized to have potential anti-tumor properties. Even so, the epidemiologic evidence addressing the relationship between cannabis use and the induction of head and neck squamous cell carcinoma is inconsistent and conflicting. Cases were patients with incident head and neck squamous cell carcinoma disease from nine medical facilities in the Greater Boston, MA area. Controls were frequency matched to cases on age, gender, and town of residence, randomly selected from Massachusetts town books. A questionnaire was adopted to collect information on lifetime cannabis use and associations appraised using unconditional logistic regression.
13 After adjusting for potential confounders (including smoking and alcohol drinking), Ten to twenty years of cannabis use was associated with a significantly reduced risk of head and neck squamous cell carcinoma Among cannabis users moderate weekly use was associated with reduced risk. The magnitude of reduced risk was more pronounced for those who started use at an older age,
13 These inverse associations did not depend on human papillomavirus sixteen antibody status. Even so, for the subjects who have the same level of smoking or alcohol drinking, we observed attenuated risk of head and neck squamous cell carcinoma among those who use cannabis compared with those who do not. Our study suggests that moderate cannabis use is associated with reduced risk of head and neck squamous cell carcinoma.
14 Association between marijuana use & the risk of bladder cancer: Results from the California Men's Health Study. Thomas et-al 2015. Urology 85: 388-393.
14 Overall thirty four thousand - forty one percent cohort members reported marijuana use, forty seven thousand, fifty seven percent reported tobacco use, twenty two thousand, twenty seven percent reported using both, and twenty three thousand - twenty nine percent used neither. Men were followed over an eleven-year period and two hundred seventy nine or 0.3 percent or developed incident bladder tumors. Among marijuana users, seventy nine developed bladder cancer in comparison to one hundred ninety men who did not report marijuana use.
14 After adjusting for age, race or ethnicity, and body mass index, using tobacco only was associated with an increased risk of bladder cancer, whereas marijuana use only was associated with a forty five percent reduction in bladder cancer incidence. Using both marijuana and tobacco was associated with a health risk.
14 Conclusion - While a cause and effect relationship has not been established, marijuana use may be inversely associated with bladder cancer risk in this group.
15 Despite the existence of conflicting reports relative to the role of the endocannabinoid system in cancer generation and progression and several reports pointing to a possible tumor-fostering immunosuppressive role of cannabinoids a large body of scientific evidences strongly supports d9THC and other cannabinoid agonists exert anti-cancer actions in preclinical models of cancer (including immunocompetent mice) through a well-established mechanism of action.
15 There is also a good evidence that cannabinoids enhance the anti-cancer action of TMZ (oral Chemo. drug) and ALK - anti-cancer drug inhibitors in mammal models of glioma (brain tumor). These observations provide preclinical proof-of-concept that cannabinoids could enhance the efficacy of classical cytotoxic (toxic to cells) drugs at least in glioblastoma (brain cancer) . Even so, additional investigations are required to analyze the efficacy of these drug combinations in other cancer types as well as to identify additional cannabinoid-based drug combinations that could be useful for the therapy of glioma (brain tumor) or other types of cancer. Likewise, further research is required to identify the precise molecular cross-talk mechanisms that become activated upon exposure of cancer cells to cannabinoids in combination with different chemotherapeutic agents.
15 Regarding patient stratification, one important step forward would be to identify which patients are potentially responsive to cannabinoid therapy. To this aim, it would be desirable that future clinical trials aimed at analyzing the anti-cancer action of cannabinoid-based medicines would include translational investigations in which specific biomarkers associated to a better or worse reaction to cannabinoid therapy could be identified.
15 In conclusion - there exist solid scientific evidence supporting that cannabinoids exhibit a remarkable anti-cancer action in preclinical models of cancer. Since these agents also show an acceptable safety profile, clinical investigations aimed at testing them as single agents or in combinational therapies are urgently needed. Results from these investigations are essential to clarify whether cannabinoids (and specifically cannabinoid-based medicines) could be helpful in the fight of cancer.
16 Cannabinoids & cancer. Natalya Kogan. 2005. Mini-Reviews in Medicinal Chemistry 5- 941-952.
16 Cannabis has been used in medicine for millennia, but it was not until 1964 that d9-tetrahydrocannabinol (d9-THC), its major psychoactive component, was isolated in pure form and its structure was extrapolated. Shortly thereafter it was synthesized and available. Even so, it took another decade until the first report on its antineoplastic action appeared. In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibitive of DNA synthesis.
16 Antiproliferative action on some other cancer cells was also found. In spite of the promising results from these early investigations, 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: Marzo's group found that phyto-cannabinoids inhibit breast cancer cell proliferation, and Guzman's group found that phyto-cannabinoids inhibit the growth of C6 glioma (brain tumor) 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.
17 Cannabinoids for cancer therapy: progress & promise. Sarfaraz et-al 2008. Cancer Research 68: 339-342.
17 Cannabinoids are a class of pharmacologic compounds that offer potential applications as anti-tumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a new strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and non habit forming cannabinoids for cancer therapy.
18 The National Cancer Institute, one of the federal government sponsored agencies, has just updated the FAQs on its website to include recent investigations on cannabis showing that it can and has killed cancer cells. These are the findings of investigations NCI have included: Cannabinoids may inhibit tumor growth by causing cell death, blocking cell growth, and blocking the development of blood vessels needed by tumors to grow. Laboratory and mammal investigations have shown that cannabinoids may be able to kill cancer cells while preserving normal cells. Cannabinoids may protect against inflammation of the colon and may have potential in reducing the risk of colon cancer, and possibly in its therapy.
18 A laboratory study of d9-THC in hepatocellular carcinoma (liver cancer) cells showed it damaged or killed the cancer cells. The same study of d-9-THC in models of liver cancer showed that it had anti-tumor effects. d9-THC has been shown to cause these effects by acting on molecules that may also be found in non-small cell lung cancer cells and breast cancer cells.
18 A laboratory study of cannabidiol in estrogen receptor positive and estrogen receptor negative breast cancer cells showed that it caused cancer cell death while having little effect on normal breast cells. investigations of metastatic breast cancer showed that cannabinoids may lessen the growth, number, and spread of tumors.
18 A laboratory study of cannabidiol in human glioma (brain tumor) cells showed that when given along with Chemo., Cannabidiol - CBD may make Chemo. more effective and increase cancer cell death without harming normal cells. Investigations showed that Cannabidiol - CBD together with d9-THC may make Chemo. such as temozolomide more effective. These investigations are considered by the NCI - National Counterintelligence Investigations as preclinical. They were all done using mammals. According to them, no clinical trials of marijuana use for the therapy of cancer in humans have been published.
18 The NCI - National Counterintelligence Investigations has included findings on peripheral benefits for cancer patients from cannabis:
18 d-9-THC and other cannabinoids stimulate appetite and can increase food intake. Cannabinoid receptors have been studied in the brain, spinal cord, and nerve endings throughout the body to understand their roles in chronic pain relief. Cannabinoids have been studied for anti-inflammatory effects that may play a function in chronic chronic pain relief.
19 How Cannabinoids Kill Cancer- There are two structures in most cells that sustains life; one is the mitochondria-organelles, and the other is the endoplasmic reticulum. The mitochondria primarily produce adenosine triphosphate (Adenotriphosphate - ATP) that provides the necessary energy. The endoplasmic reticulum (ER) is a loosely bound envelope around the cell nucleus that synthesizes metabolites and proteins directed by the nuclear DNA that nourish and sustain the cell.
19 Let us look first at tetrahydrocannabinol (THC) and observe that d9THC is a natural fit for the Cannabinoid-1 cannabinoid receptor on the cancer cell surface. When d9THC hits the receptor, the cell generates ceramide (signaling molecule) that disrupts the mitochondrial-organelles, closing off energy for the cell. The cancer cell dies, not because of cytotoxic (toxic to cells) chemicals, but because of a tiny little shift in the mitochondria-organelles.
19 In every cell there is a family of interconvertible sphingolipids (signal transmission and cell recognition molecules)that specifically manage the life and death of that cell. This profile of factors is called the Sphingolipid Rheostat (signalling and cell recognition). If ceramide is too is high, then cell death (programmed cell death - apoptosis) is imminent. If ceramide is low, the cell will be strong in its vitality.
19 Disruption of the mitochondria-organelles let out Cytochrome C and reactive oxygen species into the cytosol, hastening cell death. It is notable that this process is specific to cancer cells. Healthy cells have no reaction to d9THC at the Cannabinoid-1 receptor. The increase in ceramide also disrupts the calcium metabolism in mitochondria-organelle, causing the demise / cell death. Inside most cells, there is a cell nucleus, many mitochondria-organelles (hundreds to thousands), and various other organelles in the cytoplasm (body of cell).
19 As ceramide starts to accumulate, turning up the Sphingolipid Rheostat, it increases the mitochondria-organelles membrane pore permeability to cytochrome c, a critical protein in energy synthesis. Cytochrome C is pushed out of the mitochondria-organelles, killing the source of energy for the cell. Ceramide also causes genotoxic stress in the cancer cell nucleus generating a protein called P53, whose job it is to disrupt calcium metabolism in the mitochondria-organelles. If this weren’t enough, ceramide disrupts the cellular lysosome, the cell’s digestive system that provides nutrients for all cell actions. Ceramide, and other sphingolipids, actively inhibit pro-survival pathways in the cell leaving no possibility at all of cancer cell survival.
19 The key to this process is the accumulation of ceramide in the system. This means taking therapeutic amounts of cannabinoid extract, steadily, over a period of time, keeping metabolic pressure on this cancer cell death pathway.
19 The other cannabinoid we know is effective in killing cancer cells is cannabidiol-CBD. The main job of CBD in the cancer cell is to disrupt the endoplasmic reticulum through wrecking of the calcium metabolism, pushing calcium into the cytosol. This always results in cell death. Another pathway for Cannabidiol - CBD to affect cancer cell death is the Caspase Cascade, which breaks down proteins and peptides in the cell. When this happens the cell cannot survive. Again, these processes are specific to cancer cells, no normal cells are affected.
19 How did this pathway come to be? Why is it that the body can take a simple plant enzyme and use it for healing in many different physiological systems? This endocannabinoid system exists in all mammal life, just waiting for it’s matched exo cannabinoid activator.
19 This is interesting. Our own endocannabinoid system covers all cells and nerves; it is the messenger of information flowing between our immune system and the central nervous system . It is responsible for neuropreservation, and micro-manages the immune system. This is the main control system that maintains homeostasis: our well being.
19 Just out of curiosity, how does the work get done at the cellular level, and where does the body make the endocannabinoids? Here we see that endocannabinoids have their origin in nerve cells right at the synapse. When the body is compromised through illness or injury, it calls insistently to the endocannabinoid system and directs the immune system to bring balance. If these homeostatic systems are weakened, it should be no surprise that endocannabinoids perform the same action. It helps the body in the most natural way possible.
19 To see how this works we visualize the cannabinoid as a three dimensional molecule, where one part of the molecule is configured to fit the nerve or immune system cell receptor site just like a key in a lock. There are at least two types of cannabinoid receptor sites, Cannabinoid-1 (Central Nervous System) and Cannabinoid-2 receptor (immune). In general Cannabinoid-1 activates the Central Nervous System messaging system, and Cannabinoid-2 receptor activates the immune system, but it’s much more complex than this.
19 Both d9THC and anandamide (an endocannabinoid) activate both receptor sites. Other cannabinoids activate one or the other receptor sites. Among the strains of marijuana, C. Sativa tends toward the Cannabinoid-1 receptor, and C. indica tends toward Cannabinoid-2. So Sativa is more neuroactive, and Cannabis Indica Is more immunoactive. Another factor here is that Sativa is dominated by d9THC cannabinoids, and Cannabis Indica can be higher than Cannabis Sativa in CBD.
19 It is known that d9THC and Cannabidiol - CBD are biomimetic to anandamide (an endocannabinoid) and AG-2, that is, the body can use both interchangeably. Thus, when stress, injury, or illness - demand more from endogenous (made by the body) anandamide than can be yielded by the body, its mimetic exo cannabinoids are activated. If the stress is transitory, then the therapy can be transitory. If the demand is sustained, such as in cancer, then therapy needs to provide sustained pressure of the modulating agent on the homeostatic systems.
19 Typically Cannabidiol - CBD gravitates to the 5-HT1A and Vanilloid receptors. Cannabidiol - CBD stimulates production of anandamide (an endocannabinoid) and AG-2, endogenous (made by the body) cannabinoids that are agonists for Cannabinoid-1 and Cannabinoid-2 receptors. From there, immune system cells seek out and destroy cancer cells. Interestingly, it has been shown that d9THC and Cannabidiol - CBD cannabinoids have the ability to kill cancer cells directly without going through immune system intermediaries. d9THC and Cannabidiol - CBD hijack the lipoxygenase pathway to directly inhibit tumor growth. As a side note, it has been discovered that Cannabidiol - CBD inhibits anandamide (an endocannabinoid) reuptake. Here we see that cannabidiol helps the body preserve its own natural endocannabinoid by inhibiting the enzyme that breaks down anandamide (an endocannabinoid).
19 Research shows that d9THC is metabolized to 11-Hydroxy-THC in the liver after oral consumption. We also know that 11-Hydroxy-THC is more potent than d9THC. This suggests that marijuana via smoking, or suppository is weaker clinically than oral since it misses the first-pass in the liver to convert. If you want to avoid the mental effects, use 1:1 d9THC:Cannabidiol - CBD.
19 The CBD knocks out the mental effect while maintaining potency of the marijuana extract. My opinion is that oral marijuana extract with equal parts d9THC and CBD is the ideal cancer killer without the mental effects. The Phyto-cannabinoids work in concert to kill cancer; this is known as the entourage effect; d9THC disrupts the cancer cell mitochondria-organelles, and CBD disrupts the cell’s endoplasmic reticulum, bringing certain cell death.
19 Also good to know that hydroxy-THC has a stronger mental effect than unmodified d9THC. If the marijuana oil has not been decarboxylated (to delete the acidic carboxyl radical), then there will be no effect of the d9THC. This is the most important issue is using marijuana to kill cancer. Without decarboxylation, the d9THC cannot fit the Cannabinoid-1 receptor on the cancer cell to cause cell death.
19 In 2006, researchers in Italy showed the specifics of how Cannabidiol-CBD kills cancer. CBD stimulates what is known as the Caspase Cascade, that kills the cancer cell. First, let’s look at the nomenclature, then to how Caspase kills cancer. Caspase in an aggregate term for all cysteine-aspartic proteases.
19 The protease part meaning protein destroyer, comes from prote (from protein) and -ase (destroyer). Thus the caspases break down proteins and peptides in the moribund cell. This becomes obvious when we see caspase-3 referred to as the executioner. In the pathway of programmed cell death - apoptosis, other caspases are brought in to complete the cascade.
19 Even when the cascade is done and all the cancer is gone, Cannabidiol - CBD is still at work healing the body. Cannabidiol also shuts down the Id-1 gene; a gene that allows metastatic lesions to form. Fundamentally, this means that therapy with phyto-cannabinoids not only kills cancer through many simultaneous pathways, known as the entourage effect, but prevents metastasis. What’s not to like. One researcher says this: Cannabidiol - CBD represents the first nontoxic exogenous agent that can significantly reduced Id-1 expression in metastatic carcinoma leading to the dialing-down of tumor aggressiveness.
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