ðHgeocities.com/cannabinoidscience/Cancer.htmlgeocities.com/cannabinoidscience/Cancer.htmlelayedx€ŽÕJÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÈpœ¢“OKtext/htmlaÌþ¢“ÿÿÿÿb‰.HTue, 28 Oct 2003 14:33:35 GMT›Mozilla/4.5 (compatible; HTTrack 3.0x; Windows 98)en, *ŽÕJ¢“ Cancer Cannabinoids as Anti-Cancer Agents

There is now abundant evidence that cannabinoids can inhibit tumor growth, in a variety of tumor types, both in vitro and in vivo (Guzman, 2003). The primary cannabinoids in cannabis, THC and cannabidiol, have also proven to be potent antioxidants (Hampson et al, 1998), which may reduce some types of cancers. Surprisingly, promising experimental results were first reported by Munson et al (1975) over a quarter or a century ago. Their results showed THC dose-dependent increase in survival time and inhibition of tumor growth in mice with Lewis lung adenocarcinoma, but were little pursued until recently, following the discovery of the cannabinoid receptors.

Currently there is much research in this area, and cannabinoids have proven effective in the treatment of a variety of tumor types. For instance, Casanova et al (2003) recently showed that viability of cultured human nonmelanoma skin cancer cells, and in vivo growth of skin tumors in mice, were significantly inhibited by the CB1/CB2 agonist WIN-55,212-2 and by the selective CB2 agonist JWH-133. Inhibition appeared most potent with WIN-55,212-2, which agonizes both CB1 and CB2 receptors, rather than the selective CB2 agonist. The in vitro inhibition appeared to be selective for cancer cells and did not affect viability of non-cancer cells.  "Of interest, the cannabinoid was unable to induce any statistically significant change in the viability of MCA3D and HaCat cells, two nontransformed epidermal cell lines, and of primary human keratinocytes" (p. 46). The tumor suppression effect appeared to be due to a increase in tumor cell apoptosis, and an impairment of tumor angiogenesis.

Galve-Roperh et al (2000) demonstrated the tumor supression properties of THC and WIN-55,212-2 in rat and mice models of malignant glioma, a fatal type of brain tumor that in humans results in death within one year, even with agressive (surgical and chemotherapy) treatment. The effects were fairly dramatic, with a complete eradication of the tumors in 20-35% of the cannabinoid-treated animals, and a doubling of survival time in another third of the animals. Further, the doses used were quite low, maximum 1.0 and 0.1 mg/kg/day for THC and WIN-55,212-2, respectively. The same team reported in 2001 that glioma suppression also occurs with the selective CB2 agonist JWH-133, suggesting that the tumor-supressing cannabinoids need not be accompanied by psychoactive effects (Sanchez et al, 2001).

Cannabinoids have also been reported to inhibit the proliferation of cultured human breast and prostate cancer cells. De Petrocellis et al (1998) and Melck et al  (2000) both report that the endocannabinoids anandamide and 2-arachidonoylglycerol, as well as the potent synthetic CB1 agonist HU-210, inhibit human breast cancer cell proliferation in vitro. The effect is attenuated by a CB1 antagonist. Melck et al (2000) show the same for cultured human prostate cancer cells. Neither study tested THC, though it is very likely that it would have the same effects as the other CB1 agonists. Finally, McKallip et al (2002) demonstrated the ability of THC, HU-210, and the endocannabinoid anandamide to induce apoptosis in mouse and human leukemia and lymphoma cell lines, including primary acute lymphoblastic leukemia cells extracted from humans. Effects were demonstrated both in vitro and in vivo, and are apparently mediated by CB2 receptors, which are expressed on immune system cells. The effects were achieved also by a selective CB2 agonist JWH-015. THC not only increased survival time relative to controls, by cured 25% of the treated mice (compared to 0% survival at 20 days for the controls).
. . . we tested whether THC treatment can cure EL-4 tumor-bearing mice. To this end, mice were injected with EL-4 tumor cells (1 × 106) and then given a daily injection of 5 mg/kg THC for 14 days. The mice were observed for survival and, upon exhibiting signs of morbidity, were immediately euthanized. The results showed that treatment with THC led to a significant increase in survival (Figure 6). Interestingly, 25% of the mice survived the tumor challenge (Figure 6). Also, they were completely cured inasmuch as they were resistant to rechallenge with the specific tumor (data not shown). Taken together, these results suggest that THC can exert anticancer properties in vivo.
Interestingly, mice and rats given very doses of THC show no increase in cancer, and to the contrary showed both a reduced incidence of spontaneous cancers and an increased survival time (Chan et al, 1996). Writing in the journal Environmental Health Perspectives, Huff and Chan (2000) comment:

Experimentally, groups of 60-70 male and female rats were administered 0, 12.5, 25, or 50 mg THC/kg body weight (bw), and male and female mice were given 0, 125, 250, or 500 mg THC/kg bw in corn oil by gavage for 104-106 weeks (3,4). During this 2-year period, individual animal body weights were reduced compared to controls, although all groups consumed the same amounts of food. More importantly, survival in all THC groups of male and female rats was significantly greater than the controls. For mice, survival was comparable among groups except for the high-dose males. Clinical findings in the THC groups included lethargy followed by hyperactivity, convulsions, and seizures, which occurred typically during and immediately after dosing or handling.

In both rats and mice, no increased incidences of neoplasms were considered related to the administration of THC (3,4). In fact, for several organ systems the incidences of background tumors in these strains were actually reduced. The incidences of mammary gland fibroadenomas and uterine stromal polyps were decreased in THC groups of female rats, as were incidences of pituitary gland adenomas, interstitial cell adenomas of the testis, and pancreatic adenomas in THC-treated male rats. Concerning nonneoplastic lesions in mice, increases of thyroid gland follicular cell hyperplasia occurred in all THC groups, and increases of forestomach hyperplasia and ulcers occurred in THC groups of male mice; yet, no THC-related tumors were observed to progress from these toxic lesions. This common lack of correlation between toxicity and carcinogenicity has long been known (5-7). Regarding carcinogenic activity of THC in mice, thyroid gland follicular cell adenomas were somewhat increased only in the lowest THC-dosed group of mice (125 mg/kg); thyroid gland follicular cell adenomas were found in 0/62 control males versus 6/60, 3/61, and 1/57 mice treated with 125, 250, and 500 mg THC/kg bw, respectively, and in 4/60 control females versus 9/60, 3/60, and 1/60 mice); these were considered not significantly related to THC (3,4). However, there were significant decreases observed for both benign and malignant liver tumors in male and female mice.

. . .

Our 2-year studies (3,4) showed that the observed THC antitumor effects are not confined to the site of injection or administration, and these antitumor effects seem to affect a range of "spontaneous" tumors commonly found in rats and mice. Consequently, the THC-associated antitumor effects are systemically active and are applicable to different tumor types at different organ sites. Again, this lack of specificity might lend credence to the notion that these effects are hormonally mediated and likely related to the observed decreases in body weights. Nonetheless, there were significant reductions in total benign and malignant tumors in all organs combined for both species after THC exposure: in male rats, tumors were found in 98% of controls versus 98, 92, and 90% of groups treated with 12.5, 25, and 50 mg THC/kg bw, respectively; in female rats, tumors were found in 88% of controls versus 82, 86, and 70% of treated groups. Most strikingly, in male mice tumors were found in 73% of controls versus 55, 44, and 30% of male mice treated with 0, 125, 250, and 500 mg THC/kg bw, respectively, and in female mice, tumors were found in 77% of controls versus 52, 43, and 27% of treated groups (3,4).

References

Casanova et al, 2003. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. Journal of Clinical Investigation 111:43-50.
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 and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB(1) and CB(2)), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB(1) and the CB(2) receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.
Chan et al, 1996. Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundamental and Applied Toxicology 30(1), 109-117.
delta 9-Tetrahydrocannabinol (delta 9-THC) was studied for potential carcinogenicity in rodents because it is the principal psychoactive ingredient in marihuana and it has potential medicinal uses. delta 9-THC in corn oil was administered by gavage to groups of male and female Fischer rats and B6C3F1 mice at 0, 5, 15, 50, 150, or 500 mg/kg, 5 days a week for 13 weeks and for 13-week plus a 9-week recovery period, and to groups of rats at 0, 12.5, or 50 mg/kg and mice at 0, 125, 250, or 500 mg/kg, 5 times a week for 2 years. In all studies, mean body weights of dosed male and female rats and mice were lower than controls but feed consumptions were similar. Convulsions and hyperactivity were observed in dosed rats and mice; the onset and frequency were dose related. Serum FSH and LH levels in all dosed male rats and corticosterone levels in 25 mg/kg female rats were significantly higher than controls at 15 months in the 2-year studies. delta 9-THC administration for 13 weeks induced testicular atrophy and uterine and ovarian hypoplasia; the lesions persisted in a 9-week recovery period. In the 2-year studies, survival of dosed rats was higher than controls; that of mice was similar to controls. Incidences of testicular interstitial cell, pancreas and pituitary gland adenomas in male rats, mammary gland fibroadenoma and uterus stromal polyp in female rats, and hepatocellular adenoma/carcinoma in male and female mice were reduced in a dose-related manner. Decreased tumor incidences may be at least in part due to reduced body weights of dosed animals. Incidences of thyroid gland follicular cell hyperplasia were increased in all dosed groups of male and female mice, and follicular cell adenomas were significantly increased in the 125 mg/kg group of males, but there was no evidence of a dose-related trend in proliferative lesions of the thyroid. There was no evidence that delta 9-THC was carcinogenic in rats or mice.
De Petrocellis et al, 1998. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proceedings of the National Academy of Sciences 95(14), 8375-8380.
Anandamide was the first brain metabolite shown to act as a ligand of "central" CB1 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 microM and 83-92% maximal inhibition at 5-10 microM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 microM anandamide. The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but 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 also inhibited EFM-19 cell proliferation, whereas arachidonic acid was much less effective. 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 inhibition of EFM-19 cell proliferation. Moreover, anandamide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A. 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 microM) doses of anandamide. 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 suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.
Galve-Roperh et al, 2000. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Medicine 6, 313-319.
Delta9-Tetrahydrocannabinol, the main active component of marijuana, induces apoptosis of transformed neural cells in culture. Here, we show that intratumoral administration of Delta9-tetrahydrocannabinol and the synthetic cannabinoid agonist WIN-55,212-2 induced a considerable regression of malignant gliomas in Wistar rats and in mice deficient in recombination activating gene 2. Cannabinoid treatment did not produce any substantial neurotoxic effect in the conditions used. Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation. These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.
Guzman et al, 2001. Control of the cell survival/death decision by cannabinoids. Journal of Molecular Medicine 78, 613-625.
Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids in recent years. One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells. The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined. Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage. In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo. Breast and prostate cancer cells are also sensitive to cannabinoid-induced antiproliferation. Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson's disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors. Ongoing investigation is in search for cannabinoid-based therapeutic strategies devoid of nondesired psychotropic effects.
Guzman, 2003. Cannabinoids: Potential Anticancer Agents. Nature Reviews Cancer 3, 745 -755.

Hampson et al, 1998. Cannabidiol and D-9 tetrahydrocannabinol are neuroprotective antioxidants. Proceedings of the National Academy of Sciences 95, pp. 8268–8273.
The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (-)Delta9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-D-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-D-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.
Huff and Chan, 2000. Antitumor effects of THC. Environmental Health Perspectives 108 (10), A442-A443.

Jacobsson et al, 2001. Inhibition of Rat C6 Glioma Cell Proliferation by Endogenous and Synthetic Cannabinoids. Relative Involvement of Cannabinoid and Vanilloid Receptors. Journal of Pharmacology and Experimental Therapeutics 299, 951-959.
The effects of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) upon rat C6 glioma cell proliferation were examined and compared with a series of synthetic cannabinoids and related compounds. Cells were treated with the compounds each day and cell proliferation was monitored for up to 5 days of exposure. AEA time- and concentration-dependently inhibited C6 cell proliferation. After 4 days of treatment, AEA and 2-AG inhibited C6 cell proliferation with similar potencies (IC50 values of 1.6 and 1.8 µM, respectively), whereas palmitoylethanolamide showed no significant antiproliferative effects at concentrations up to 10 µM. The antiproliferative effects of both AEA and 2-AG were blocked completely by a combination of antagonists at cannabinoid receptors (SR141716A and SR144528 or AM251 and AM630) and vanilloid receptors (capsazepine) as well as by -tocopherol (0.1 and 10 µM), and reduced by calpeptin (10 µM) and fumonisin B1 (10 µM), but not by L-cycloserine (1 and 100 µM). CP 55,940, JW015, olvanil, and arachidonoyl-serotonin were all found to affect C6 glioma cell proliferation (IC50 values of 5.6, 3.2, 5.5, and 1.6 µM, respectively), but the inhibition could not be blocked by cannabinoid + vanilloid receptor antagonists. It is concluded that the antiproliferative effects of the endocannabinoids upon C6 cells are brought about by a mechanism involving combined activation of both vanilloid receptors and to a lesser extent cannabinoid receptors, and leading to oxidative stress and calpain activation. However, there is at present no obvious universal mechanism whereby plant-derived, synthetic, and endogenous cannabinoids affect cell viability and proliferation.
McKallip et al, 2002. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100:627-634.
In the current study, we examined whether ligation of CB2 receptors would lead to induction of apoptosis in tumors of immune origin and whether CB2 agonist could be used to treat such cancers. Exposure of murine tumors EL-4, LSA, and P815 to delta-9-tetrahydrocannabinol (THC) in vitro led to a significant reduction in cell viability and an increase in apoptosis. Exposure of EL-4 tumor cells to the synthetic cannabinoid HU-210 and the endogenous cannabinoid anandamide led to significant induction of apoptosis, whereas exposure to WIN55212 was not effective. Treatment of EL-4 tumor-bearing mice with THC in vivo led to a significant reduction in tumor load, increase in tumor-cell apoptosis, and increase in survival of tumor-bearing mice. Examination of a number of human leukemia and lymphoma cell lines, including Jurkat, Molt-4, and Sup-T1, revealed that they expressed CB2 receptors but not CB1. These human tumor cells were also susceptible to apoptosis induced by THC, HU-210, anandamide, and the CB2-selective agonist JWH-015. This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist SR144528 partially reversed the THC-induced apoptosis. Culture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis. Together, the current data demonstrate that CB2 cannabinoid receptors expressed on malignancies of the immune system may serve as potential targets for the induction of apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel anticancer agents to selectively target and kill tumors of immune origin.
Melck et al, 2000. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 141:118-126.
Anandamide and 2-arachidonoylglycerol (2-AG), two endogenous ligands of the CB1 and CB2 cannabinoid receptor subtypes, inhibit the proliferation of PRL-responsive human breast cancer cells (HBCCs) through down-regulation of the long form of the PRL receptor (PRLr). Here we report that 1) anandamide and 2-AG inhibit the nerve growth factor (NGF)-induced proliferation of HBCCs through suppression of the levels of NGF Trk receptors; 2) inhibition of PRLr levels results in inhibition of the proliferation of other PRL-responsive cells, the prostate cancer DU-145 cell line; and 3) CB1-like cannabinoid receptors are expressed in HBCCs and DU-145 cells and mediate the inhibition of cell proliferation and Trk/PRLr expression. Beta-NGF-induced HBCC proliferation was potently inhibited (IC50 = 50-600 nM) by the synthetic cannabinoid HU-210, 2-AG, anandamide, and its metabolically stable analogs, but not by the anandamide congener, palmitoylethanolamide, or the selective agonist of CB2 cannabinoid receptors, BML-190. The effect of anandamide was blocked by the CB1 receptor antagonist, SR141716A, but not by the CB2 receptor antagonist, SR144528. Anandamide and HU-210 exerted a strong inhibition of the levels of NGF Trk receptors as detected by Western immunoblotting; this effect was reversed by SR141716A. When induced by exogenous PRL, the proliferation of prostate DU-145 cells was potently inhibited (IC50 = 100-300 nM) by anandamide, 2-AG, and HU-210. Anandamide also down-regulated the levels of PRLr in DU-145 cells. SR141716A attenuated these two effects of anandamide. HBCCs and DU-145 cells were shown to contain 1) transcripts for CB1 and, to a lesser extent, CB2 cannabinoid receptors, 2) specific binding sites for [3H]SR141716A that could be displaced by anandamide, and 3) a CB1 receptor-immunoreactive protein. These findings suggest that endogenous cannabinoids and CB1 receptor agonists are potential negative effectors of PRL- and NGF-induced biological responses, at least in some cancer cells.
Munson et al, 1975. Antineoplastic activity of cannabinoids. Journal of the National Cancer Institute 55(3).
Lewis lung adenocarcinoma growth was retarded by the oral administration of delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta-9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta-8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta-9-THC, delta-8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg;, respectively), whereas CBD did not. Delta-9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 X DBA/2) F (BDF) mice hosting the L1210 murine leukemia. However, delta-9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta-8-THC and delta-9-THC showed a dose-dependent (10 -4 10 -7) inhibition (80-20%, respectively) of tritiated thymidine and 14C -uridine uptake into these cells. CBD was active only in high concentrations (10 -4).
Recht et al, 2001. Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. Biochem Pharmacol 2001;62(6):755-763.
One of the endogenous transformation products of tetrahydrocannabinol (THC) is THC-11-oic acid, and ajulemic acid (AJA; dimethylheptyl-THC-11-oic acid) is a side-chain synthetic analog of THC-11-oic acid. In preclinical studies, AJA has been found to be a potent anti-inflammatory agent without psychoactive properties. Based on recent reports suggesting antitumor effects of cannabinoids (CBs), we assessed the potential of AJA as an antitumor agent. AJA proved to be approximately one-half as potent as THC in inhibiting tumor growth in vitro against a variety of neoplastic cell lines. However, its in vitro effects lasted longer. The antitumor effect was stereospecific, suggesting receptor mediation. Unlike THC, however, whose effect was blocked by both CB(1) and CB(2) receptor antagonists, the effect of AJA was inhibited by only the CB(2) antagonist. Additionally, incubation of C6 glioma cells with AJA resulted in the formation of lipid droplets, the number of which increased over time; this effect was noted to a much greater extent after AJA than after THC and was not seen in WI-38 cells, a human normal fibroblast cell line. Analysis of incorporation of radiolabeled fatty acids revealed a marked accumulation of triglycerides in AJA-treated cells at concentrations that produced tumor growth inhibition. Finally, AJA, administered p.o. to nude mice at a dosage several orders of magnitude below that which produces toxicity, inhibited the growth of subcutaneously implanted U87 human glioma cells modestly but significantly. We conclude that AJA acts to produce significant antitumor activity and effects its actions primarily via CB(2) receptors. Its very favorable toxicity profile, including lack of psychoactivity, makes it suitable for chronic usage. Further studies are warranted to determine its optimal role as an antitumor agent.
Sánchez et al, 2001. Inhibition of Glioma Growth in Vivo by Selective Activation of the CB2 Cannabinoid Receptor. Cancer Research 61, 5784-5789.
The development of new therapeutic strategies is essential for the management of gliomas, one of the most malignant forms of cancer. We have shown previously that the growth of the rat glioma C6 cell line is inhibited by psychoactive cannabinoids (I. Galve-Roperh et al., Nat. Med., 6: 313–319, 2000). These compounds act on the brain and some other organs through the widely expressed CB1 receptor. By contrast, the other cannabinoid receptor subtype, the CB2 receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB2 agonist JWH-133 at 50 µg/day to Rag-2-/- mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells. The selective involvement of the CB2 receptor in this action was evidenced by: (a) the prevention by the CB2 antagonist SR144528 but not the CB1 antagonist SR141716; (b) the down-regulation of the CB2 receptor but not the CB1 receptor in the tumors; and (c) the absence of typical CB1-mediated psychotropic side effects. Cannabinoid receptor expression was subsequently examined in biopsies from human astrocytomas. A full 70% (26 of 37) of the human astrocytomas analyzed expressed significant levels of cannabinoid receptors. Of interest, the extent of CB2 receptor expression was directly related with tumor malignancy. In addition, the growth of grade IV human astrocytoma cells in Rag-2-/- mice was completely blocked by JWH-133 administration at 50 µg/day. Experiments carried out with C6 glioma cells in culture evidenced the internalization of the CB2 but not the CB1 receptor upon JWH-133 challenge and showed that selective activation of the CB2 receptor signaled apoptosis via enhanced ceramide synthesis de novo. These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.
Walsh et al, 2003. Established and potential therapeutic applications of cannabinoids in oncology. Supportive Care in Cancer 11(3), 137-143.
Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.