Jacob Bell
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Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis
GIUSEPPE PORTELLA*,2, CHIARA LAEZZA*,2, PAOLO LACCETTI*, LUCIANO DE PETROCELLIS" , VINCENZO DI MARZO"¡,3 and MAURIZIO BIFULCO*,§,3
*," , "¡Endocannabinoid Research Group,
* Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, and Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," Università di Napoli "Federico II,
" Istituto di Cibernetica and
"¡ Istituto di Chimica Biomolecolare, C.N.R., Comprensorio Olivetti, 80078, Pozzuoli (NA), Italy; and
§ Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, 84084 Fisciano (SA), Italy
3Correspondence: V.D.M., Istituto di Chimica Biomolecolare, C.N.R., Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli (NA), Italy; E-mail: vdimarzo@icmib.na.cnr.it and M.B., Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, via Ponte Don Melillo, 84084 Fisciano (SA), Italy. E-mail: maubiful@unina.it
SPECIFIC AIMS
Stimulation of cannabinoid CB1 receptors inhibits the growth of xenograft tumors of thyroid origin by blocking the activity of p21ras. We looked at the effect of the metabolically stable endocannabinoid analog 2-methyl-arachidonyl-2`-fluoro-ethylamide (Met-F-AEA) on the growth of an established carcinoma in athymic mice. We studied the effect of CB1 stimulation by Met-F-AEA on factors involved in tumor angiogenesis and metastasis, on proliferation of rat thyroid metastatic cells in vitro and on the formation of metastatic nodules in vivo.
PRINCIPAL FINDINGS
1. Met-F-AEA inhibits the growth of an established tumor in vivo
Since the effect of Met-F-AEA on incipient tumors has been analyzed, to evaluate the effects of this compound on already established tumors, 45 nude mice were injected subcutaneously with K-ras-transformed FRTL-5 cells (Ki-Mol cells). Twenty days later, when tumors were clearly detectable, saline solution containing Met-F-AEA (0.5 mg/kg/dose) was injected in the peritumoral area on days 2 and 5 of a 7 day cycle for 4 wk. Met-F-AEA treatment induced a drastic reduction in tumor volume with respect to the vehicle control-treated mice (not shown). This effect was significantly inhibited by the CB1 receptor antagonist SR141716A (0.7 mg/kg/dose, s.c. intratumor, coadministered with Met-F-AEA; P<0.01 by ANOVA).
2. Effect of Met-F-AEA on the expression of endogenous pro- and anti-angiogenic factors
Since we observed that the tumors from Met-F-AEA-treated mice were paler than the tumors from untreated mice and because we noted previously that Met-F-AEA is able to block p21ras activity via CB1 receptors, we investigated whether this compound could inhibit angiogenesis by affecting the expression of the vascular endothelial growth factor (VEGF), which in turn depends on the p21ras activity. Western blot analysis of proteins from treated or untreated tumors (Fig. 1 ) showed that VEGF levels were dramatically reduced by Met-F-AEA treatment. In addition, Met-F-AEA treatment reduced the expression of a VEGF receptor (Flt-1 or VEGFR-1) (Fig. 1) . These inhibitory effects of Met-F-AEA were attenuated by the selective CB1 receptor antagonist, SR141716A (Fig. 1) , strongly suggesting the involvement of CB1 receptors in the anti-VEGF action of the compound, and were observed in Ki-Mol cells in vitro. The cyclin-dependent kinase inhibitor p27(kip1) is another protein suggested to play a role as a proangiogenic factor and is under the negative control of the ras oncogene in proliferating human thyroid cells. We found that Met-F-AEA treatment of tumors and Ki-Mol cells increased p27(kip1) levels and that this effect was attenuated by the selective CB1 receptor antagonist, SR141716A (not shown).
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Figure 1. Met-F-AEA (AEA) modulates the expression of signals involved in angiogenesis and metastasis in xenograft tumors and transformed cells. Left panel: Met-F-AEA reduces VEGF and VEGFR-1 levels in treated tumors. Tumor samples from the experiments were excised from animals at the end of the treatments, homogenized, and proteins were extracted and used for Western immunoblotting. Right panel: Met-F-AEA reduces VEGF and VEGFR-1 levels in KiMol cells. KiMol cells were incubated with Met-F-AEA (10 µM) for 24 h. VEGF and VEGFR-1 expression were analyzed by Western immunoblotting. The same amount of proteins (50 µg) was loaded in each lane. The data are representative of 3 experiments yielding similar results. Bands were analyzed by densitometry scanning, which, after background subtraction, revealed statistically significant differences.
3. Effect of Met-F-AEA on metastatic cells
Since underexpression of p27(kip1) has been correlated with increased spreading of thyroid cancer cells to lymph nodes and VEGF itself has been implicated in cancer cell metastasis, we investigated the effect of Met-F-AEA on metastatic processes. We compared the anti-proliferative action of this compound on two other cell lines derived from a rat thyroid carcinoma (TK-6 cells) or its lung metastasis (MPTK-6 cells, which display a highly more malignant phenotype with respect to TK-6 cells). Four day treatment with Met-F-AEA was able to inhibit the proliferation of both neoplastic thyroid cell lines. However, the growth of metastasis-derived cells was inhibited more efficaciously than that of primary thyroid carcinoma-derived cells (62.0±7.0 vs. 38.0±8.0% inhibition, means±SE, n=3; P<0.05 by ANOVA), and this effect was accompanied by a stronger up-regulation of CB1 receptor levels in MPTK-6 cells than in TK-6 (not shown).
4. Effect of Met-F-AEA on the formation of metastatic nodules in the Lewis lung carcinoma model
The above data prompted us to test the effects of Met-F-AEA in vivo on the induction of metastatic foci in mice lungs after intra-paw injection of the highly metastatic Lewis lung carcinoma (3LL) cells. A dramatic inhibitory effect of Met-F-AEA was observed against lung metastatic nodules induced by 3LL cells (Fig. 2 ). Even those few metastatic nodules observed in Met-F-AEA-treated animals were smaller than those present in control animals. The metastatic growth inhibitory effect was blocked by the CB1 receptor antagonist SR141716A (Fig. 2 , P<0.01 by ANOVA).
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Figure 2. Met-F-AEA (AEA) blocks the metastasis of Lewis lung carcinoma cells. Mice left paws were injected with the highly metastatic Lewis lung carcinoma (3LL) cells. Mice were then treated with Met-F-AEA (0.5 mg/kg/dose, i.p. every 72 h) or Met-F-AEA + SR141716A (0.7 mg/kg/dose, i.p.). Differences in the number of lung nodules were analyzed at the end of the experiment, 21 days after inoculation, and were statistically significant (P<0.01 by ANOVA) between vehicle- and Met-F-AEA-treated mice and between Met-F-AEA-treated and Met-F-AEA+SR141716A-treated mice. Results shown are representative of 2 independent experiments.
CONCLUSIONS AND SIGNIFICANCE
We recently reported that stimulation of cannabinoid CB1 receptors by the metabolically stable endocannabinoid analog Met-F-AEA, by inhibiting p21ras activity, prevents the growth of v-K-ras-transformed rat thyroid cells both in vitro and in vivo when injected concomitantly to transformed cells into athymic mice. In the present study we found that Met-F-AEA is able to block the growth of already established tumors, thus indicating that anandamide-based drugs may be efficacious therapeutic drugs for the inhibition of cancer cells growth. As we observed earlier that Met-F-AEA is not capable of inducing apoptosis of our neoplastic cell line model, a likely means by which CB1 stimulation leads to blockade of the growth of established tumors might be the inhibition of tumor neo-angiogenesis. VEGF is an important proangiogenic factor of human thyroid tumors and is known to be up-regulated by p21ras. Since activation of CB1 receptors by Met-F-AEA blocks p21ras activity, the effect of this compound on VEGF signaling was analyzed, showing a dramatic reduction of VEGF expression. We also found that Met-F-AEA suppressed the expression of the VEGF receptor Flt-1 (also known as VEGFR-1), which plays a crucial role in mediating VEGF-induced neo-angiogenesis and endothelial cell proliferation. Finally, Met-F-AEA up-regulated the levels of the cyclin-dependent kinase inhibitor p27(kip1), another signal that has been recognized as a possible endogenous suppressor of angiogenesis and whose expression is inhibited by p21ras. These effects, observed both in Met-F-AEA-treated tumors in vivo and in rat thyroid cancer cells in vitro and significantly attenuated by the CB1 receptor antagonist SR141716A, strongly suggest that stimulation of CB1 receptors might lead to inhibition of tumor angiogenesis and metastatic spreading in vivo (Fig. 3 ).
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Figure 3. Possible mechanisms for cannabinoid receptor control of cancer growth, angiogenesis, and metastasis based on findings reported here and previously. CB1 receptor stimulation leads to inhibition of VEGF and VGEF receptor (Flt-1) expression, possibly by inhibiting p21ras activity and increasing p27(kip1) levels. These effects result in inhibition of endothelial cell migration and proliferation and, hence, of neo-angiogenesis. The stimulatory effect on p27(kip1) might contribute to Met-F-AEA-induced inhibition of tumor progression via inhibition of cancer cell proliferation and spreading. Since VEGF has been proposed to act as an autocrine-paracrine signal mediating, in part, cancer cell proliferation and metastasis, the inhibition of VEGF signaling might contribute to the Met-F-AEA effects on cancer growth and metastasis described here. Solid arrows denote activation, broken arrows denote inhibition.
While a direct effect of cannabinoids on new vessel formation and endothelial cell migration and apoptosis was reported during this study, we gained direct evidence for the effect of Met-F-AEA on tumor metastasis by finding that 4 day treatment with Met-F-AEA inhibited the proliferation of the metastasis-derived thyroid cancer MPTK-6 cell line more efficaciously than in the primary thyroid cancer-derived TK-6 cell line. This effect was probably because 4 day treatment with Met-F-AEA led to a much stronger up-regulation of CB1 receptors in MPTK-6 cells than in TK-6 cells, and suggests that activation of these receptors might cause inhibition of metastasis in vivo. This hypothesis was supported by using an in vivo model of metastatic spreading, that is the formation of lung nodules after inoculation of Lewis lung carcinoma cells. We found that Met-F-AEA produced a reduction in the number and size of metastatic nodes in this model in a way that was again counteracted by the CB1 receptor antagonist. %In conclusion, we have demonstrated for the first time that CB1 receptor stimulation 1) may inhibit tumor angiogenesis and metastasis by both suppressing the expression of VEGF and of its Flt-1 receptor and enhancing p27(kip1) levels; and 2) does interfere with metastatic processes in vitro and in vivo. Our data indicate that the endocannabinoid system might be targeted pharmacologically to block at multiple levels the molecular and cellular processes intervening in cancer growth and spreading (Fig. 3) .
FOOTNOTES
1 To read the full text of this article, go to https://www.fasebj.org/cgi/doi/10.1096/fj.02-1129fje; doi: 10.1096/fj.02-1129fje
2 G.P. and C.L. contributed equally to this work.
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Source: Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis
GIUSEPPE PORTELLA*,2, CHIARA LAEZZA*,2, PAOLO LACCETTI*, LUCIANO DE PETROCELLIS" , VINCENZO DI MARZO"¡,3 and MAURIZIO BIFULCO*,§,3
*," , "¡Endocannabinoid Research Group,
* Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, and Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," Università di Napoli "Federico II,
" Istituto di Cibernetica and
"¡ Istituto di Chimica Biomolecolare, C.N.R., Comprensorio Olivetti, 80078, Pozzuoli (NA), Italy; and
§ Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, 84084 Fisciano (SA), Italy
3Correspondence: V.D.M., Istituto di Chimica Biomolecolare, C.N.R., Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli (NA), Italy; E-mail: vdimarzo@icmib.na.cnr.it and M.B., Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, via Ponte Don Melillo, 84084 Fisciano (SA), Italy. E-mail: maubiful@unina.it
SPECIFIC AIMS
Stimulation of cannabinoid CB1 receptors inhibits the growth of xenograft tumors of thyroid origin by blocking the activity of p21ras. We looked at the effect of the metabolically stable endocannabinoid analog 2-methyl-arachidonyl-2`-fluoro-ethylamide (Met-F-AEA) on the growth of an established carcinoma in athymic mice. We studied the effect of CB1 stimulation by Met-F-AEA on factors involved in tumor angiogenesis and metastasis, on proliferation of rat thyroid metastatic cells in vitro and on the formation of metastatic nodules in vivo.
PRINCIPAL FINDINGS
1. Met-F-AEA inhibits the growth of an established tumor in vivo
Since the effect of Met-F-AEA on incipient tumors has been analyzed, to evaluate the effects of this compound on already established tumors, 45 nude mice were injected subcutaneously with K-ras-transformed FRTL-5 cells (Ki-Mol cells). Twenty days later, when tumors were clearly detectable, saline solution containing Met-F-AEA (0.5 mg/kg/dose) was injected in the peritumoral area on days 2 and 5 of a 7 day cycle for 4 wk. Met-F-AEA treatment induced a drastic reduction in tumor volume with respect to the vehicle control-treated mice (not shown). This effect was significantly inhibited by the CB1 receptor antagonist SR141716A (0.7 mg/kg/dose, s.c. intratumor, coadministered with Met-F-AEA; P<0.01 by ANOVA).
2. Effect of Met-F-AEA on the expression of endogenous pro- and anti-angiogenic factors
Since we observed that the tumors from Met-F-AEA-treated mice were paler than the tumors from untreated mice and because we noted previously that Met-F-AEA is able to block p21ras activity via CB1 receptors, we investigated whether this compound could inhibit angiogenesis by affecting the expression of the vascular endothelial growth factor (VEGF), which in turn depends on the p21ras activity. Western blot analysis of proteins from treated or untreated tumors (Fig. 1 ) showed that VEGF levels were dramatically reduced by Met-F-AEA treatment. In addition, Met-F-AEA treatment reduced the expression of a VEGF receptor (Flt-1 or VEGFR-1) (Fig. 1) . These inhibitory effects of Met-F-AEA were attenuated by the selective CB1 receptor antagonist, SR141716A (Fig. 1) , strongly suggesting the involvement of CB1 receptors in the anti-VEGF action of the compound, and were observed in Ki-Mol cells in vitro. The cyclin-dependent kinase inhibitor p27(kip1) is another protein suggested to play a role as a proangiogenic factor and is under the negative control of the ras oncogene in proliferating human thyroid cells. We found that Met-F-AEA treatment of tumors and Ki-Mol cells increased p27(kip1) levels and that this effect was attenuated by the selective CB1 receptor antagonist, SR141716A (not shown).
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Figure 1. Met-F-AEA (AEA) modulates the expression of signals involved in angiogenesis and metastasis in xenograft tumors and transformed cells. Left panel: Met-F-AEA reduces VEGF and VEGFR-1 levels in treated tumors. Tumor samples from the experiments were excised from animals at the end of the treatments, homogenized, and proteins were extracted and used for Western immunoblotting. Right panel: Met-F-AEA reduces VEGF and VEGFR-1 levels in KiMol cells. KiMol cells were incubated with Met-F-AEA (10 µM) for 24 h. VEGF and VEGFR-1 expression were analyzed by Western immunoblotting. The same amount of proteins (50 µg) was loaded in each lane. The data are representative of 3 experiments yielding similar results. Bands were analyzed by densitometry scanning, which, after background subtraction, revealed statistically significant differences.
3. Effect of Met-F-AEA on metastatic cells
Since underexpression of p27(kip1) has been correlated with increased spreading of thyroid cancer cells to lymph nodes and VEGF itself has been implicated in cancer cell metastasis, we investigated the effect of Met-F-AEA on metastatic processes. We compared the anti-proliferative action of this compound on two other cell lines derived from a rat thyroid carcinoma (TK-6 cells) or its lung metastasis (MPTK-6 cells, which display a highly more malignant phenotype with respect to TK-6 cells). Four day treatment with Met-F-AEA was able to inhibit the proliferation of both neoplastic thyroid cell lines. However, the growth of metastasis-derived cells was inhibited more efficaciously than that of primary thyroid carcinoma-derived cells (62.0±7.0 vs. 38.0±8.0% inhibition, means±SE, n=3; P<0.05 by ANOVA), and this effect was accompanied by a stronger up-regulation of CB1 receptor levels in MPTK-6 cells than in TK-6 (not shown).
4. Effect of Met-F-AEA on the formation of metastatic nodules in the Lewis lung carcinoma model
The above data prompted us to test the effects of Met-F-AEA in vivo on the induction of metastatic foci in mice lungs after intra-paw injection of the highly metastatic Lewis lung carcinoma (3LL) cells. A dramatic inhibitory effect of Met-F-AEA was observed against lung metastatic nodules induced by 3LL cells (Fig. 2 ). Even those few metastatic nodules observed in Met-F-AEA-treated animals were smaller than those present in control animals. The metastatic growth inhibitory effect was blocked by the CB1 receptor antagonist SR141716A (Fig. 2 , P<0.01 by ANOVA).
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Figure 2. Met-F-AEA (AEA) blocks the metastasis of Lewis lung carcinoma cells. Mice left paws were injected with the highly metastatic Lewis lung carcinoma (3LL) cells. Mice were then treated with Met-F-AEA (0.5 mg/kg/dose, i.p. every 72 h) or Met-F-AEA + SR141716A (0.7 mg/kg/dose, i.p.). Differences in the number of lung nodules were analyzed at the end of the experiment, 21 days after inoculation, and were statistically significant (P<0.01 by ANOVA) between vehicle- and Met-F-AEA-treated mice and between Met-F-AEA-treated and Met-F-AEA+SR141716A-treated mice. Results shown are representative of 2 independent experiments.
CONCLUSIONS AND SIGNIFICANCE
We recently reported that stimulation of cannabinoid CB1 receptors by the metabolically stable endocannabinoid analog Met-F-AEA, by inhibiting p21ras activity, prevents the growth of v-K-ras-transformed rat thyroid cells both in vitro and in vivo when injected concomitantly to transformed cells into athymic mice. In the present study we found that Met-F-AEA is able to block the growth of already established tumors, thus indicating that anandamide-based drugs may be efficacious therapeutic drugs for the inhibition of cancer cells growth. As we observed earlier that Met-F-AEA is not capable of inducing apoptosis of our neoplastic cell line model, a likely means by which CB1 stimulation leads to blockade of the growth of established tumors might be the inhibition of tumor neo-angiogenesis. VEGF is an important proangiogenic factor of human thyroid tumors and is known to be up-regulated by p21ras. Since activation of CB1 receptors by Met-F-AEA blocks p21ras activity, the effect of this compound on VEGF signaling was analyzed, showing a dramatic reduction of VEGF expression. We also found that Met-F-AEA suppressed the expression of the VEGF receptor Flt-1 (also known as VEGFR-1), which plays a crucial role in mediating VEGF-induced neo-angiogenesis and endothelial cell proliferation. Finally, Met-F-AEA up-regulated the levels of the cyclin-dependent kinase inhibitor p27(kip1), another signal that has been recognized as a possible endogenous suppressor of angiogenesis and whose expression is inhibited by p21ras. These effects, observed both in Met-F-AEA-treated tumors in vivo and in rat thyroid cancer cells in vitro and significantly attenuated by the CB1 receptor antagonist SR141716A, strongly suggest that stimulation of CB1 receptors might lead to inhibition of tumor angiogenesis and metastatic spreading in vivo (Fig. 3 ).
View larger version (42K):
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Figure 3. Possible mechanisms for cannabinoid receptor control of cancer growth, angiogenesis, and metastasis based on findings reported here and previously. CB1 receptor stimulation leads to inhibition of VEGF and VGEF receptor (Flt-1) expression, possibly by inhibiting p21ras activity and increasing p27(kip1) levels. These effects result in inhibition of endothelial cell migration and proliferation and, hence, of neo-angiogenesis. The stimulatory effect on p27(kip1) might contribute to Met-F-AEA-induced inhibition of tumor progression via inhibition of cancer cell proliferation and spreading. Since VEGF has been proposed to act as an autocrine-paracrine signal mediating, in part, cancer cell proliferation and metastasis, the inhibition of VEGF signaling might contribute to the Met-F-AEA effects on cancer growth and metastasis described here. Solid arrows denote activation, broken arrows denote inhibition.
While a direct effect of cannabinoids on new vessel formation and endothelial cell migration and apoptosis was reported during this study, we gained direct evidence for the effect of Met-F-AEA on tumor metastasis by finding that 4 day treatment with Met-F-AEA inhibited the proliferation of the metastasis-derived thyroid cancer MPTK-6 cell line more efficaciously than in the primary thyroid cancer-derived TK-6 cell line. This effect was probably because 4 day treatment with Met-F-AEA led to a much stronger up-regulation of CB1 receptors in MPTK-6 cells than in TK-6 cells, and suggests that activation of these receptors might cause inhibition of metastasis in vivo. This hypothesis was supported by using an in vivo model of metastatic spreading, that is the formation of lung nodules after inoculation of Lewis lung carcinoma cells. We found that Met-F-AEA produced a reduction in the number and size of metastatic nodes in this model in a way that was again counteracted by the CB1 receptor antagonist. %In conclusion, we have demonstrated for the first time that CB1 receptor stimulation 1) may inhibit tumor angiogenesis and metastasis by both suppressing the expression of VEGF and of its Flt-1 receptor and enhancing p27(kip1) levels; and 2) does interfere with metastatic processes in vitro and in vivo. Our data indicate that the endocannabinoid system might be targeted pharmacologically to block at multiple levels the molecular and cellular processes intervening in cancer growth and spreading (Fig. 3) .
FOOTNOTES
1 To read the full text of this article, go to https://www.fasebj.org/cgi/doi/10.1096/fj.02-1129fje; doi: 10.1096/fj.02-1129fje
2 G.P. and C.L. contributed equally to this work.
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Articles citing this article
Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis Blood May 19, 2011 117:5541-5550
Abstract
Full Text
Full Text (PDF)
Cannabinoid Receptors, CB1 and CB2, as Novel Targets for Inhibition of Non-Small Cell Lung Cancer Growth and Metastasis Cancer Prev Res January 1, 2011 4:65-75
Abstract
Full Text
Full Text (PDF)
Antitumorigenic Effects of Cannabinoids beyond Apoptosis J. Pharmacol. Exp. Ther. February 1, 2010 332:336-344
Abstract
Full Text
Full Text (PDF)
The anandamide analog, Met-F-AEA, controls human breast cancer cell migration via the RHOA/RHO kinase signaling pathway Endocr Relat Cancer December 1, 2008 15:965-974
Abstract
Full Text
Full Text (PDF)
Endocannabinoids in endocrine and related tumours Endocr Relat Cancer June 1, 2008 15:391-408
Abstract
Full Text
Full Text (PDF)
Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression J. Cell Sci. May 15, 2008 121:1704-1717
Abstract
Full Text
Full Text (PDF)
Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression Cancer Res. March 15, 2008 68:1945-1952
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The Cannabinoid CB1 Receptor Antagonist Rimonabant (SR141716) Inhibits Human Breast Cancer Cell Proliferation through a Lipid Raft-Mediated Mechanism Mol. Pharmacol. October 1, 2006 70:1298-1306
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Full Text
Full Text (PDF)
The Endocannabinoid System as an Emerging Target of Pharmacotherapy Pharmacol. Rev. September 1, 2006 58:389-462
Abstract
Full Text
Full Text (PDF)
A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells Mol. Pharmacol. July 1, 2006 70:51-59
Abstract
Full Text
Full Text (PDF)
Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress-Related Genes. Cancer Res. July 1, 2006 66:6748-6755
Abstract
Full Text
Full Text (PDF)
{Delta}9-Tetrahydrocannabinol Inhibits Cell Cycle Progression in Human Breast Cancer Cells through Cdc2 Regulation. Cancer Res. July 1, 2006 66:6615-6621
Abstract
Full Text
Full Text (PDF)
N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation FASEB J. March 1, 2006 20:412-418
Abstract
Full Text
Full Text (PDF)
Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas Cancer Res. August 15, 2004 64:5617-5623
Source: Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis
