Full Pubmed Study Here

Angiogenesis is a highly regulated multistep process that involves endothelial cell chemotactic migration, invasion, proliferation, differentiation into tubular capillaries, and the production of a basement membrane around the vessels (; ). In this study, CBD exhibited potent anti-angiogenic properties, inhibiting HUVEC growth, migration and invasion in vitro as well as angiogenesis in the Matrigel sponge assay in vivo. Molecular studies in vitro demonstrated that CBD exerts its effects through the down-regulation of several angiogenic mechanisms. Taken together, these data suggest that CBD has great potential as a new anti-angiogenic drug.

Our results demonstrated that CBD was effective in inhibiting endothelial cell proliferation without inducing endothelial cell apoptosis or necrosis, suggesting a cytostatic action. Several chemotherapeutic drugs have anti-angiogenic properties only at near or fully cytotoxic concentrations; therefore, their clinical relevance is controversial. Interestingly, CBD did not induce HUVEC apoptosis or necrosis even at the highest dose tested (12 µM). Several anti-angiogenic molecules inhibit endothelial cell proliferation, without exerting any cytotoxic action and can even inhibit apoptosis in endothelial cells (; ; ). This seems to be in contrast to their effects on tumour cells, where often these compounds are cytotoxic, at least at high doses. However, this may depend on several characteristics of tumour cells, including chronic stress related to high-level production of oxygen and other radicals, metabolic alterations and oncogene dependence (). Further cellular stress in tumour cells pushes the cell over the threshold and into apoptosis, whereas in normal cells, this may act as a form of ‘preconditioning’ stimulus that renders the cells more resistant to subsequent insults ().

CBD’s lack of cytotoxicity towards endothelial cells is quite different from that reported in previous studies with other cannabinoids (). In these studies, endothelial cell cytotoxicity was considered a potential mechanism of action. Our data suggest that, unlike other cannabinoids, the effects of CBD are not due to endothelial cell toxicity but rather to modulation of intracellular pathways leading to a decrease in several pro-angiogenic factors.

CBD showed potent inhibition of endothelial cell migration, both in the scratch wound-healing assay and, with an even stronger effect, in the Boyden chamber assay. The different efficacy of CBD in these tests could be ascribed to the different sensitivity of the assays, since the wound-healing assay is generally less sensitive than the Boyden chamber. Moreover, the use of primary fresh HUVECs in the Boyden chamber in comparison with the commercially available cells employed in the wound-healing assay could account for the different potency observed. However, in our hands, CBD elicited significant effects on migration at concentrations lower than those causing 50% inhibition of proliferation (9 µM and 1 µM, respectively, in wound healing and Boyden chamber assays versus IC50 value of 10 µM in the MTT assay run in parallel to the migration tests). We previously demonstrated the same order of potency of CBD on U87-MG glioma cell proliferation versus invasion (). In agreement with these results, ) showed that CBD was more potent at inhibiting U251 invasiveness compared to their proliferation. Thus, similar to glioma, CBD is highly potent at inhibiting endothelial cell migration compared to proliferation, suggesting that factors influencing cell migration and invasion may represent its primary targets.

In line with this, our molecular investigation showed that CBD affected the expression of several prominent factors involved in primary vascular endothelial cell functions; in particular compounds that induce invasion and migration, which included MMP2 and MMP9, TIMP1, SerpinE1/PAI1, uPA, CXCL16, IL-8, ET-1 and PDGF-AA.

CBD inhibited MMP2 and MMP9, two fundamental proteases that, through the remodelling of the extracellular matrix and basement membrane, are involved in distinct vascular events, and whose levels are increased in numerous malignancies, including glioma (; ; ).

CBD down-regulated the expression of TIMP1, a stromal factor with multiple functions. TIMPs are commonly described as negative regulators of MMPs. ) showed that TIMP1 is an inhibitor of high-grade glioma invasion. In line with this, ) recently reported a CBD-driven increase in TIMP1 in lung cancer cells that correlated with diminished invasiveness. Nevertheless, there is increasing evidence to suggest that TIMPs are multifunctional proteins, possessing a dual role in regulating cell proliferation and angiogenesis. In vitro, TIMP1 promotes growth of human keratinocytes and several other cell types (; ), inhibits apoptosis (; ; ) and regulates angiogenesis (; ). Moreover, increased expression of TIMP1 protein has been observed in multiple tumour types, including breast, colon, gastric and lung cancers, as well as in lymphoma and carcinomas of unknown primary origin (; ; ; ; ; ; ).

Based on these considerations, it is noteworthy that inhibition of proteins such as MMP2 and MMP9 and TIMP1 further confirms the wide spectrum of CBD action on MMP and TIMP molecules, key factors in cell motility, invasion and proliferation, and suggests a complex picture through which CBD can impair cell growth and invasion.

In addition to the MMP/TIMP system, CBD also down-regulated the uPA and the plasminogen activator inhibitor SerpinE1/PAI-1, two important factors in extracellular matrix remodelling and consequent angiogenesis. The uPA plays a pivotal role in the degradation of extracellular matrix, and suppression of uPA and uPAR by shRNA attenuates angiogenin-mediated angiogenesis in endothelial and glioblastoma cell lines (). Thus, CBD shares similarities with other therapeutic approaches that, by inhibiting the uPA/uPAR functions, have been shown to possess anti-angiogenic and anti-tumour effects (for review, see ).

Since SerpinE1/PAI-1 inhibits uPA, low levels of this protein would be expected to favour cell growth. However, recent data have revealed a two-faced role in the modulation of apoptosis in tumour cells in comparison with non-tumour cells. At present, the reason for these discrepant effects is still unclear and some recent reports point to other multifunctional roles of this protein in angiogenesis, invasiveness and cell adhesion ().

CBD also significantly inhibited two potent angiogenic factors: the chemokines CXCL16 and IL-8 (). Stimulation of HUVECs with CXCL16 leads to increases in cell proliferation, chemotactic motility and network formation (), whereas IL-8 can induce angiogenesis through both direct and indirect mechanisms (; ; ). The decreased level of both chemokines following CBD treatment would be consistent with its in vitro and in vivo anti-angiogenic effects.

Two growth factors were also down-regulated by CBD: ET-1 and PDGF-AA. ETs modulate various stages of neovascularization. Increased levels of ET-1 and its cognate receptor are significantly associated with microvessel density and VEGF expression in tumour cells, whereas its down-regulation correlates well with diminished endothelial cell growth and migration ().

PDGF-AA is a member of the well-known PDGF family that exerts its angiogenic effect in endothelial cells by binding to a specific protein tyrosine kinase receptor, which in its turn engages several signalling molecules involved in multiple cellular and developmental responses.

Taken together, these observations suggest a broad effect of CBD on vascular endothelial cell biology. This wide spectrum modulation of angiogenesis-related factors leads to a decreased ability of endothelial cells to properly form new vessels in vitro and, to an even more prominent extent, impaired angiogenesis in in vivoplugs.

However, the molecular mechanism through which CBD exerts these effects still remains unknown. Vascular endothelial cells express various functional receptors for cannabinoids, including the CB1 receptor (), the CB2 receptor (), the tentative abnormal CBD receptor (), the TRP receptors (; ; ) and the PPARγ (; ): each of these could, at least in part, be involved in CBD anti-angiogenic effects. These receptors control important cell functions such as migration (; ), survival (), vascular tone (; ) and tumour-derived endothelial cell migration (). Recently, blockade of the CB1 receptor has been closely linked to inhibition of angiogenesis (). Our present data do not allow us to indicate a receptor-dependent versus -independent mechanism of CBD in HUVECs. Since both cannabinoid-dependent (; ; ; Ramer et al., 2010a,b; ) and -independent (; ; ) mechanisms were previously shown for CBD anti-tumour effects, it is also possible that its anti-angiogenic activity may be due to a receptor-independent mechanism, involving different primary cellular targets. In line with this, recent studies (; ) have demonstrated that the anti-invasive and anti-proliferative effects of CBD in breast cancer are closely associated with inhibition of Id-1, an inhibitor of basic helix-loop-helix transcription factors that is over-expressed in tumour cells. Id proteins play a vital role in regulating angiogenesis during embryonic development and tumourigenesis and ectopic Id-1 expression in HUVECs leads to increased migration of the cells, while suppression of its endogenous expression results in reduced migration (). Thus, Id-1 could represent a key signalling pathway for CBD in HUVECs.

In conclusion, our results indicate that CBD exerts a potent anti-angiogenic effect by widely affecting several pathways involved in this process. Its dual effect on both tumour and endothelial cells further suggests that CBD could represent a potential effective agent in cancer therapy.

References

  • Albini A, Fontanini G, Masiello L, Tacchetti C, Bigini D, Luzzi P, et al. Angiogenic potential in vivo by Kaposi’s sarcoma cell-free supernatants and HIV-1 tat product: inhibition of KS-like lesions by tissue inhibitor of metalloproteinase-2. AIDS. 1994;8:1237–1244. [PubMed]
  • Albini A, Brigati C, Ventura A, Lorusso G, Pinter M, Morini M, et al. Angiostatin anti-angiogenesis requires IL-12: the innate immune system as a key target. J Transl Med. 2009;14:7–5. [PMC free article] [PubMed]
  • Albini A, Indraccolo S, Noonan DM, Pfeffer U. Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive drugs. Clin Exp Metastasis. 2010;27:419–439. [PubMed]
  • Alexander A, Smith PF, Rosengren RJ. Cannabinoids in the treatment of cancer. Cancer Lett. 2009;285:6–12.[PubMed]
  • Alexander CM, Howard EW, Bissell MJ, Werb Z. Rescue of mammary epithelial apoptosis and entactin degradation by a tissue inhibitor of metalloproteinase-1 transgene. J Cell Biol. 1996;135:1669–1677.[PMC free article] [PubMed]
  • Alexander SPH, Mathie A, Peters JA. Guide to receptors and channels (GRAC), 5th edition. Br J Pharmacol. 2011;164(Suppl. 1):S1–S324. [PMC free article] [PubMed]
  • Aviello G, Romano B, Borrelli F, Capasso R, Gallo L, Piscitelli F, et al. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med. 2012 DOI: 10.1007/s00109-011-0856-x [Epub ahead of print] [PubMed]
  • Bagnato A, Spinella F, Rosanò L. The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapy. Can J Physiol Pharmacol. 2008;86:473–484. [PubMed]
  • Bátkai S, Járai Z, Wagner JA, Goparaju SK, Varga K, Liu J, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med. 2001;7:827–832. [PubMed]
  • Benelli R, Morini M, Carrozzino F, Ferrari N, Minghelli S, Santi L, et al. Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J. 2002;16:267–269. [PubMed]
  • Benelli R, Albini A, Noonan D. Neutrophils and angiogenesis: potential initiators of the angiogenic cascade. In: Cassatella MA, editor. The Neutrophil: An Emerging Regulator of Inflammatory and Immune Response. Basel: Karger; 2003. pp. 167–181. [PubMed]
  • Bertaux B, Hornebeck W, Eisen AZ, Dubertret L. Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases. J Invest Dermatol. 1991;97:679–685. [PubMed]
  • Blázquez C, Casanova ML, Planas A, Gómez del Pulgar T, Villanueva C, Fernández-Aceñero MJ, et al. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 2003;17:529–531. [PubMed]
  • Blázquez C, González-Feria L, Alvarez L, Haro A, Casanova ML, Guzmán M. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res. 2004;64:5617–5623. [PubMed]
  • Blázquez C, Carracedo A, Barrado L, Real PJ, Fernández-Luna JL, Velasco G, et al. Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J. 2006;20:2633–2635. [PubMed]
  • Cantelmo AR, Cammarota R, Noonan DM, Focaccetti C, Comoglio PM, Prat M, et al. Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth. Oncogene. 2010;29:5286–5298.[PMC free article] [PubMed]
  • Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest. 2003;111:43–50. [PMC free article] [PubMed]
  • Cattaneo MG, Chini B, Vicentini LM. Oxytocin stimulates migration and invasion in human endothelial cells. Br J Pharmacol. 2008;153:728–736. [PMC free article] [PubMed]
  • Cattaneo MG, Lucci G, Vicentini LM. Oxytocin stimulates in vitro angiogenesis via a Pyk-2/Src-dependent mechanism. Exp Cell Res. 2009;315:3210–3219. [PubMed]
  • Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer. 2010;10:505–514. [PubMed]
  • Curry FR, Glass CA. TRP channels and the regulation of vascular permeability: new insights from the lung microvasculature. Circ Res. 2006;99:915–917. [PubMed]
  • De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163:1479–1494. [PMC free article] [PubMed]
  • Fassina G, Venè R, Morini M, Minghelli S, Benelli R, Noonan DM, et al. Mechanisms of inhibition of tumor angiogenesis and vascular tumor growth by epigallocatechin-3-gallate. Clin Cancer Res. 2004;10:4865–4873. [PubMed]
  • Ferrari N, Tosetti F, De Flora S, Donatelli F, Noonan DM, Albini A. Diet-derived phytochemicals: from cancer chemoprevention to cardio-oncological prevention. Curr Drug Targets. 2010;12:1909–1924.[PubMed]
  • Fiorio Pla A, Avanzato D, Munaron L, Ambudkar IS. Ion channels and transporters in cancer. 6. Vascularizing the tumor: TRP channels as molecular targets. Am J Physiol Cell Physiol. 2012;302:C9–C15. [PubMed]
  • Flygare J, Sander B. The endocannabinoid system in cancer-potential therapeutic target? Semin Cancer Biol. 2008;18:176–189. [PubMed]
  • Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.[PubMed]
  • Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007;6:273–286. [PubMed]
  • Freimuth N, Ramer R, Hinz B. Antitumorigenic effects of cannabinoids beyond apoptosis. J Pharmacol Exp Ther. 2010;332:336–344. [PubMed]
  • Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant – do they exist? Br J Pharmacol. 2010;160:523–529. [PMC free article] [PubMed]
  • Golech SA, McCarron RM, Chen Y, Bembry J, Lenz F, Mechoulam R, et al. Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res Mol Brain Res. 2004;132:87–92. [PubMed]
  • Gouyer V, Conti M, Devos P, Zerimech F, Copin MC, Créme E, et al. Tissue inhibitor of metalloproteinase-1 is an independent predictor of prognosis in patients with non-small cell lung carcinoma who undergo resection with curative intent. Cancer. 2005;103:1676–1684. [PubMed]
  • Grant DS, Tashiro K, Segui-Real B, Yamada Y, Martin GR, Kleinman HK. Two different laminin domains mediate the differentiation of human endothelial cells into capillary-like structures in vitro. Cell. 1989;58:933–943. [PubMed]
  • Guedez L, Stetler-Stevenson WG, Wolff L, Wang J, Fukushima P, Mansoor A, et al. In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1. J Clin Invest. 1998;102:2002–2010. [PMC free article] [PubMed]
  • Guedez L, McMarlin AJ, Kingma DW, Bennett TA, Stetler-Stevenson M, Stetler-Stevenson WG. Tissue inhibitor of metalloproteinase-1 alters the tumorigenicity of Burkitt’s lymphoma via divergent effects of tumor growth and angiogenesis. Am J Pathol. 2001;158:1207–1215. [PMC free article] [PubMed]
  • Guindon J, Hohmann AG. The endocannabinoid system and cancer: therapeutic implication. Br J Pharmacol. 2011;163:1447–1463. [PMC free article] [PubMed]
  • Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K. Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett. 1992;298:29–32. [PubMed]
  • Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. NC3Rs Reporting Guidelines Working Group. Br J Pharmacol. 2010;160:1577–1579. [PMC free article] [PubMed]
  • Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunological criteria. J Clin Invest. 1973;52:2745–2756.[PMC free article] [PubMed]
  • Járai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A. 1999;96:14136–14141. [PMC free article] [PubMed]
  • Karavasilis V, Malamou-Mitsi V, Briasoulis E, Tsanou E, Kitsou E, Kalofonos H, et al. Matrix metalloproteinases in carcinoma of unknown primary. Cancer. 2005;104:2282–2287. [PubMed]
  • Kesisis G, Broxterman H, Giaccone G. Angiogenesis inhibitors. Drug selectivity and target specificity. Curr Pharm Des. 2007;13:2795–2809. [PubMed]
  • Korff T, Augustin HG. Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation. J Cell Biol. 1998;143:1341–1352. [PMC free article] [PubMed]
  • Korff T, Augustin HG. Tensional forces in fibrillar extracellular matrices control directional capillary sprouting. J Cell Sci. 1999;112:3249–3258. [PubMed]
  • Kwan HY, Huang Y, Yao X. TRP channels in endothelial function and dysfunction. Biochim Biophys Acta. 2007;1772:907–914. [PubMed]
  • Lafleur MA, Handsley MM, Knäuper V, Murphy G, Edwards DR. Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type matrix metalloproteinases (MT-MMPs) J Cell Sci. 2002;115:3427–3428. [PubMed]
  • Lai Y, Shen Y, Liu XH, Zhang Y, Zeng Y, Liu YF. Interleukin-8 induces the endothelial cell migration through the activation of phosphoinositide 3-kinase-Rac1/RhoA pathway. Int J Biol Sci. 2011;7:782–791.[PMC free article] [PubMed]
  • Li G, Fridman R, Kim HR. Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. Cancer Res. 1999;59:6267–6275. [PubMed]
  • Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006;318:1375–1387. [PubMed]
  • Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, et al. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J. 2000;346:835–840. [PMC free article][PubMed]
  • Lorusso G, Vannini N, Sogno I, Generoso L, Garbisa S, Noonan DM, et al. Mechanisms of hyperforin as an anti-angiogenic angioprevention agent. Eur J Cancer. 2009;45:1474–1484. [PubMed]
  • Marcu JP, Christian RT, Lau D, Zielinski AJ, Horowitz MP, Lee J, et al. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther. 2010;9:180–189. [PMC free article] [PubMed]
  • Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther. 2004;308:838–845.[PubMed]
  • Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, Parolaro D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci. 2006;63:2057–2066.[PubMed]
  • Massi P, Valenti M, Vaccani A, Gasperi V, Perletti G, Marras E, et al. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem. 2008;104:1091–1100. [PubMed]
  • McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther. 2007;6:2921–2927. [PubMed]
  • McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, et al. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat. 2011;129:37–47. [PMC free article] [PubMed]
  • McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, et al. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood. 2002;100:627–634. [PubMed]
  • McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M. Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol. 2006;70:897–908. [PubMed]
  • McGrath J, Drummond G, McLachlan E, Kilkenny C, Wainwright C. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1573–1576. [PMC free article][PubMed]
  • Mimori K, Mori M, Shiraishi T, Fujie T, Baba K, Haraguchi M, et al. Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer. 1997;76:531–536. [PMC free article][PubMed]
  • Mo FM, Offertáler L, Kunos G. Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1. Eur J Pharmacol. 2004;489:21–27. [PubMed]
  • Nasser JA, Falavigna A, Ferraz F, Duigou G, Bruce J. Transcription analysis of TIMP-1 and NM23-H1 genes in glioma cell invasion. Arq Neuropsiquiatr. 2006;64:774–780. [PubMed]
  • Noonan DM, De Lerma Barbaro A, Vannini N, Mortara L, Albini A. Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev. 2008;27:31–40. [PubMed]
  • Noonan DM, Ventura A, Bruno A, Pagani A, Albini A. The angiogenic switch: role of immune cells. In: Wang E, Marincola F, editors. Immunologic Signatures of Rejection. New York: Springer; 2011a. pp. 57–75.
  • Noonan DM, Sogno I, Albini A. Plants and plant-derived products as cancer chemopreventive agents. In: Bagetta G, Cosentino M, Corasaniti MT, Sakurada S, editors. Herbal Medicines: Development and Validation of Plant-Derived Medicines for Human Health. Boca Raton, FL: CRC Press Inc; 2011b. pp. 285–306.
  • O’Sullivan SE, Kendall DA. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology. 2010;215:611–616. [PubMed]
  • O’Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol. 2009;612:61–68. [PubMed]
  • Pisanti S, Borselli C, Oliviero O, Laezza C, Gazzerro P, Bifulco M. Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy. J Cell Physiol. 2007;211:495–503. [PubMed]
  • Pisanti S, Picardi P, Prota L, Proto MC, Laezza C, McGuire PG, et al. Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis. Blood. 2011;117:5541–5550. [PubMed]
  • Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V, Bifulco M. Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J. 2003;17:1771–1773. [PubMed]
  • Preet A, Ganju RK, Groopman JE. Delta9-tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene. 2008;27:339–346. [PubMed]
  • Qiu J, Wang G, Hu J, Peng Q, Zheng Y. Id1-induced inhibition of p53 facilitates endothelial cell migration and tube formation by regulating the expression of beta1-integrin. Mol Cell Biochem. 2011;357:125–133.[PubMed]
  • Rabquer BJ, Tsou PS, Hou Y, Thirunavukkarasu E, Haines GK, 3rd, Impens AJ, et al. Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis. Arthritis Res Ther. 2011;13:R18. [PMC free article] [PubMed]
  • Raghu H, Lakka SS, Gondi CS, Mohanam S, Dinh DH, Gujrati M, et al. Suppression of uPA and uPAR attenuates angiogenin mediated angiogenesis in endothelial and glioblastoma cell lines. PLoS ONE. 2010;5:e12458. [PMC free article] [PubMed]
  • Ramer R, Merkord J, Rohde H, Hinz B. Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. Biochem Pharmacol. 2010a;79:955–966. [PubMed]
  • Ramer R, Rohde A, Merkord J, Rohde H, Hinz B. Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells. Pharm Res. 2010b;27:2162–2174. [PubMed]
  • Ree AH, Florenes VA, Berg JP, Maelandsmo GM, Nesland JM, Fodstad O. High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases. Clin Cancer Res. 1997;3:1623–1628. [PubMed]
  • Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344–1364. [PMC free article] [PubMed]
  • Schrohl AS, Holten-Andersen MN, Peters HA, Look MP, Meijer-van Gelder ME, Klijn JG, et al. Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer. Clin Cancer Res. 2004;10:2289–2298. [PubMed]
  • Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther. 2011;10:1161–1172. [PubMed]
  • Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S, Salazar M, García-Taboada E, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther. 2011;10:90–103. [PubMed]
  • Ulisse S, Baldini E, Sorrenti S, D’Armiento M. The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr Cancer Drug Targets. 2009;9:32–71. [PubMed]
  • Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol. 2005;144:1032–1036.[PMC free article] [PubMed]
  • Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature. 1997;390:518–521. [PubMed]
  • Yokoyama Y, Xin B, Shigeto T, Mizunuma H. Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers. J Cancer Res Clin Oncol. 2011;137:1219–1228. [PubMed]
  • Yoshiji J, Harris SR, Raso E, Gomez DE, Lindsay CK, Shibuya M, et al. Mammary carcinoma cells overexpressing tissue inhibitor of metalloproteinases-1 show enhanced vascular endothelial growth factor expression. Int J Cancer. 1998;75:81–87. [PubMed]
  • Zeng ZS, Cohen AM, Zhang ZF, Stetler-Stevenson W, Guillem JG. Elevated tissue inhibitor of metalloproteinase I RNA in colorectal cancer stroma correlates with lymph node and distant metastases. Clin Cancer Res. 1995;1:899–906. [PubMed]
  • Zhuge X, Murayama T, Arai H, Yamauchi R, Tanaka M, Shimaoka T, et al. CXCL16 is a novel angiogenic factor for human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2005;331:1295–1300.[PubMed]
Share This

Share This

Share this post with your friends!