A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells

Kogan, Natalya M.; Blázquez, Cristina; Álvarez, Luis; Gallily, Ruth; Schlesinger, Michael; Guzmán, Manuel; Mechoulam, Raphael

doi:10.1124/mol.105.021089

Cited by 65 publications

(42 citation statements)

References 34 publications

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“…Similar suppressive effects of cannabinoid were also observed against gliomas in vitro (41) and human colon carcinoma xenografts in nude mice (42). The present results supported the view that cannabinoid exhibits highly effective antiangiogenic action and has a synergetic effect in combination with ADM. Additionally, previous studies revealed that VEGF is vital for tumor-associated microvascular invasion as an angiogenic factor (43,44) and its expression was shown to be associated with the distant metastasis of tumor cells (45,46).…”

Section: Discussionsupporting

confidence: 88%

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

Niu

Zhao

et al. 2015

Oncology Letters

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Abstract. Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. The present study aimed to identify novel therapeutic strategies for osteosarcoma, by assessing the antitumor activity of the cannabinoid WIN-55,212-2 and its combined effect with adriamycin (ADM) against the MG-63 human osteosarcoma cell line. To evaluate the antiproliferative action of these molecules, a Cell Counting kit-8 (CCK-8) assay was used. The ability of cannabinoid to inhibit the migration, invasion and angiogenic activity of MG-63 cells were assessed by scratch, Transwell ® chamber and angiogenesis assays, respectively, in vitro. To examine the alterations in expression of targeted genes, quantitative polymerase chain reaction and western blot analysis were used. The administration of cannabinoid combined with ADM was demonstrated to inhibit the growth of MG-63 cells, resulting in a cell viability of 32.12±3.13%, which was significantly lower (P<0.05) compared with the cell viability following treatment with cannabinoid (70.86±7.55%) and ADM (62.87±5.98%) alone. Greater antimetastasis and antiangiogenic activities were also observed following the coadministration of the two agents compared with individual treatments and controls. In addition, the expression levels of Notch-1, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in MG-63 cells were downregulated following the treatments with cannabinoid alone or in combination with ADM. In conclusion, the present findings demonstrated that cannabinoid WIN-55,212-2 may significantly potentiate the antiproliferative, antimetastasis and antiangiogenic effects of ADM against MG-63 cells via the downregulation of Notch-1, MMP-2 and VEGF. These findings may offer a novel strategy for the treatment of osteosarcoma.

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Section: Discussionsupporting

confidence: 88%

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

Niu

Zhao

et al. 2015

Oncology Letters

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“…In a previous study, HU-331 was shown to exert an antiangiogenic effect accompanied by apoptosis of endothelial cells (31). In contrast, in the present study, HU-331 did not cause death of human cancer cells by eliciting apoptosis.…”

Section: Discussioncontrasting

confidence: 81%

HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor

Kogan¹,

Schlesinger²,

Priel

et al. 2007

Molecular Cancer Therapeutics

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Anthracyclines, a large group of quinonoid compounds, are used to treat some forms of cancer. Although highly effective in cancer therapy, the mechanism of action of these compounds is not specific; they act on cancer and other cells by numerous mechanisms. A new anticancer quinone (HU-331) was synthesized from cannabidiol. It shows significant high efficacy against human cancer cell lines in vitro and against in vivo tumor grafts in nude mice. In this study, we investigated its mode of action and present evidence on its unique mechanism. HU-331 does not cause cancer cell cycle arrest, cell apoptosis, or caspase activation. HU-331 -caused cell death of human cancer cell lines is not mediated by reactive oxygen intermediates/species, as exposure to HU-331 failed to elicit the generation of reactive oxygen species. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations but has only a slight nonsignificant effect on DNA topoisomerase I action. The cannabinoid quinone HU-331 is a highly specific inhibitor of topoisomerase II, compared with most known anticancer quinones. It might represent a new potent anticancer drug. [Mol Cancer Ther 2007;6(1):173 -83]

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“…Therefore, it is not likely that the antioxidant effect of the CBD would interfere with its chemotherapeutic efficacy. In addition, CBD by itself and its derivative Hu-331 (Kogan et al, 2006) have also been demonstrated to exert various antitumor properties (e.g., inhibition of growth and migration of various cancer cell lines, inhibition of angiogenesis, and attenuation of the growth of xenograft tumors in mice; Vaccani et al, 2005;Kogan et al, 2006;Ligresti et al, 2006;McAllister et al, 2007), which rather predict additive and/or synergistic anticancer effect(s) of CBD in combination with various chemotherapeutic agents, undoubtedly deserving further exploration in upcoming studies.…”

Section: Cannabidiol For Cisplatin-induced Nephrotoxicity 711mentioning

confidence: 99%

Cannabidiol Attenuates Cisplatin-Induced Nephrotoxicity by Decreasing Oxidative/Nitrosative Stress, Inflammation, and Cell Death

Pān

Mukhopadhyay

Rajesh

et al. 2008

J Pharmacol Exp Ther

222

166

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The platinum compound cisplatin is one of the most potent chemotherapy agents available to treat various malignancies. Nephrotoxicity is a common complication of cisplatin chemotherapy, which involves increased oxidative and nitrosative stress, limiting its clinical use. In this study, we have investigated the effects of a nonpsychoactive cannabinoid cannabidiol, which was reported to exert antioxidant effects and has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in patients in a mouse model of cisplatin-induced nephropathy. Cisplatin induced increased expression of superoxide-generating enzymes RENOX (NOX4) and NOX1, enhanced reactive oxygen species generation, inducible nitric-oxide synthase expression, nitrotyrosine formation, apoptosis (caspase-3/7 activity, DNA fragmentation, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining), poly(ADP-ribose) polymerase activity, and inflammation (tumor necrosis factor-␣ and interleukin-1␤) in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum blood urea nitrogen and creatinine levels) 72 h after the administration of the drug. Treatment of mice with cannabidiol markedly attenuated the cisplatin-induced oxidative/nitrosative stress, inflammation, and cell death in the kidney, and it improved renal function. Thus, our results suggest that cannabidiol may represent a promising new protective strategy against cisplatin-induced nephrotoxicity.

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A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells

Cited by 65 publications

References 34 publications

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor

Cannabidiol Attenuates Cisplatin-Induced Nephrotoxicity by Decreasing Oxidative/Nitrosative Stress, Inflammation, and Cell Death

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