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Can cannabidiol inhibit angiogenesis in colon cancer?

Comparative Clinical Pathology volume 28, pages 165–172 (2019)Cite this article

Abstract

Colon cancer is the third most common human malignancy and a main cause of death worldwide. The current study was carried out to investigate the effects of cannabidiol, a cannabinoid, on angiogenesis and cell death in mice with experimental colon cancer induced by injection of CT26 cell line. Fifty male BALB/c mice were assigned randomly to five study groups, including: (1) negative control, (2) cancer control, (3) cancer vehicle control, (3) cancer treatment (1 mg/kg cannabidiol), and (5) cancer treatment (5 mg/kg cannabidiol). Treatment responses were evaluated based on histopathological examination, the expression of vascular endothelial growth factor (VEGF) gene, measurement of interleukins (ILs 6 and 8), oxidative stress parameters (glutathione peroxidase, glutathione reductase, superoxide dismutase serum activities, total antioxidant capacity, and malondialdehyde levels). In the present study, CBD reduced VEGF gene expression, decreased serum levels of IL6, IL8, and malondialdehyde, and increased antioxidant enzyme activity in mice with colon cancer. Moreover, cannabidiol induced apoptosis and reduced cellular pleomorphism. Cannabidiol can be potentially considered as an anti-colon cancer medicine as it exerts an inhibitory effect on angiogenesis, tumor growth, and metastasis through reducing VEGF gene expression, decreasing cytokines, and increasing antioxidant enzyme activities.

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References

  • Ashokkumar P, Sudhandiran G (2008) Protective role of luteolin on the status of lipid peroxidation and antioxidant defense against azoxymethane-induced experimental colon carcinogenesis. Biomed Pharmacother 62:590–597

    Article  CAS  PubMed  Google Scholar 

  • Aviello G, Romano B, Borrelli F, Capasso R, Gallo L, Piscitelli F, Di Marzo V, Izzo AA (2012) Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med 90:925–934

    Article  CAS  PubMed  Google Scholar 

  • Badjatia N, Satyam A, Singh P, Seth A, Sharma A (2010) Altered antioxidant status and lipid peroxidation in Indian patients with urothelial bladder carcinoma. Urol Oncol: seminars and original investigations. Elsevier, pp 360–367

  • Blázquez C, González-Feria L, Álvarez L, Haro A, Casanova ML, Guzmán M (2004) Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64:5617–5623

    Article  PubMed  Google Scholar 

  • Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490

    Article  CAS  PubMed  Google Scholar 

  • Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202

    Article  Google Scholar 

  • de Andrés PJ, Illera JC, Cáceres S, Díez L, Pérez-Alenza MD, Pena L (2013) Increased levels of interleukins 8 and 10 as findings of canine inflammatory mammary cancer. Vet Immunol Immunopathol 152:245–251

    Article  CAS  PubMed  Google Scholar 

  • Folkman J (1972) Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175:409–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franceschi S, Wild CP (2013) Meeting the global demands of epidemiologic transition–the indispensable role of cancer prevention. Mol Oncol 7:1–13

    Article  PubMed  Google Scholar 

  • Freimuth N, Ramer R, Hinz B (2010) Antitumorigenic effects of cannabinoids beyond apoptosis. J Pharmacol Exp Ther 332:336–344

    Article  CAS  PubMed  Google Scholar 

  • Gallily R, Even-Chen T, Katzavian G, Lehmann D, Dagan A, Mechoulam R (2003) γ-Irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk Lymphoma 44:1767–1773

    Article  CAS  PubMed  Google Scholar 

  • Greenhough A, Patsos HA, Williams AC, Paraskeva C (2007) The cannabinoid δ9-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int J Cancer 121:2172–2180

    Article  CAS  PubMed  Google Scholar 

  • Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gurudath S, Naik RM, Ganapathy K, Guruprasad Y, Sujatha D, Pai A (2012) Superoxide dismutase and glutathione peroxidase in oral submucous fibrosis, oral leukoplakia, and oral cancer: a comparative study. J Orofac Sci 4:114

    Article  CAS  Google Scholar 

  • Hosseini-Zijoud SM, Ebadi SA, Goodarzi MT, Hedayati M, Abbasalipourkabir R, Mahjoob MP, Poorolajal J, Zicker F, Sheikh N (2016) Lipid peroxidation and antioxidant status in patients with medullary thyroid carcinoma: a case-control study. J Clin Diagn Res 10:BC04

    CAS  PubMed  PubMed Central  Google Scholar 

  • Knüpfer H, Preiss R (2010) Serum interleukin-6 levels in colorectal cancer patients—a summary of published results. Int J Color Dis 25:135–140

    Article  Google Scholar 

  • Lokeshkumar B, Sathishkumar V, Nandakumar N, Rengarajan T, Madankumar A, Balasubramanian MP (2015) Anti-oxidative effect of Myrtenal in prevention and treatment of Colon Cancer induced by 1, 2-dimethyl hydrazine (DMH) in experimental animals. Biomol Ther 23:471–478

    Article  CAS  Google Scholar 

  • Lukhele ST, Motadi LR (2016) Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and induce apoptosis in cervical cancer cells. BMC Complement Altern Med 16:335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lurje G, Zhang W, Schultheis A, Yang D, Groshen S, Hendifar A, Husain H, Gordon M, Nagashima F, Chang H (2008) Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann Oncol 19:1734–1741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lykkesfeldt J (2001) Determination of malondialdehyde as dithiobarbituric acid adduct in biological samples by HPLC with fluorescence detection: comparison with ultraviolet-visible spectrophotometry. Clin Chem 47:1725–1727

    CAS  Google Scholar 

  • Manju V, Sailaja JK, Nalini N (2002) Circulating lipid peroxidation and antioxidant status in cervical cancer patients: a case-control study. Clin Biochem 35:621–625

    Article  CAS  PubMed  Google Scholar 

  • Mantovani A (2007) Cancer: an infernal triangle. Nature 448:547–548

    Article  CAS  PubMed  Google Scholar 

  • Marcu JP, Christian RT, Lau D, Zielinski AJ, Horowitz MP, Lee J, Pakdel A, Allison J, Limbad C, Moore DH, Yount GL, Desprez PY, McAllister SD (2010) Cannabidiol enhances the inhibitory effects of Δ9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther 9:180–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez P-Y (2007) Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther 6:2921–2927

    Article  CAS  PubMed  Google Scholar 

  • Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years⊥. J Nat Prod 70:461–477

    Article  CAS  Google Scholar 

  • Noonan DM, Sogno I, Albini A (2011) Plants and plant-derived products as cancer chemopreventive agents. In: Bagetta G, Cosentino M, Corasaniti MT, Sakurada S (eds) Herbal medicines: development and validation of plant-derived medicines for human health. CRC Press Inc, Boca Raton, pp 285–306

    Google Scholar 

  • Ortega A, García-Hernández V, Ruiz-García E, Meneses-García A, Herrera-Gómez A, Aguilar-Ponce J, Montes-Servín E, Prospero-García O, Del Angel S (2016) Comparing the effects of endogenous and synthetic cannabinoid receptor agonists on survival of gastric cancer cells. Life Sci 165:56–62

    Article  CAS  PubMed  Google Scholar 

  • Pan H, Mukhopadhyay P, Rajesh M, Patel V, Mukhopadhyay B, Gao B, Haskó G, Pacher P (2009) Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/Nitrosative stress, inflammation, and cell death. J Pharmacol Exp Ther 328:708–714

    Article  CAS  PubMed  Google Scholar 

  • Rabquer BJ, Tsou PS, Hou Y, Thirunavukkarasu E, Haines GK, Impens AJ, Phillips K, Kahaleh B, Seibold JR, Koch AE (2011) Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis. Arthritis Res Ther 13:R18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajesh M, Mukhopadhyay P, Bátkai S, Patel V, Saito K, Matsumoto S, Kashiwaya Y, Horváth B, Mukhopadhyay B, Becker L (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol 56:2115–2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramer R, Merkord J, Rohde H, Hinz B (2010) Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. Biochem Pharmacol 79:955–966

    Article  CAS  PubMed  Google Scholar 

  • Ray G, Batra S, Shukla NK, Deo S, Raina V, Ashok S, Husain SA (2000) Lipid peroxidation, free radical production and antioxidant status in breast cancer. Breast Cancer Res Treat 59:163–170

    Article  CAS  PubMed  Google Scholar 

  • Ribatti D, Vacca A, Presta M (2000) The discovery of angiogenic factors: a historical review. Gen Pharmacol 35:227–231

    Article  CAS  PubMed  Google Scholar 

  • Scott KA, Dalgleish AG, Liu WM (2014) The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther 13:2955–2967

    Article  CAS  PubMed  Google Scholar 

  • Sergio R, Hernández L, Gallegos M (2015) Cannabinoids in Neuroinflammation, oxidative stress and neuro excitotoxicity. Pharm Anal Acta 6:2

    Google Scholar 

  • Shahi PK, Pineda IF (2008) Tumoral angiogenesis: review of the literature. Cancer Investig 26:104–108

    Article  CAS  Google Scholar 

  • Sharma M, Hudson JB, Adomat H, Guns E, Cox ME (2014) In vitro anticancer activity of plant-derived cannabidiol on prostate cancer cell lines. Pharmacol Pharm 5:806–820

    Article  CAS  Google Scholar 

  • Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics. CA Cancer J Clin 64:9–29

    Article  PubMed  Google Scholar 

  • Takeda S, Okajima S, Miyoshi H, Yoshida K, Okamoto Y, Okada T, Amamoto T, Watanabe K, Omiecinski CJ, Aramaki H (2012) Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett 214:314–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van der Poel HG (2007) Molecular markers in the diagnosis of prostate cancer. Crit Rev Oncol Hematol 61:104–139

    Article  PubMed  Google Scholar 

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Funding

The authors would like to thank the Research Council of Shiraz University and School of Veterinary Medicine, Shiraz University for their financial and technical support of this study (Grant No. 71-GR-VT-5).

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Authors and Affiliations

  1. Department of Clinical Studies, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

    Masoumeh Honarmand & Saeed Nazifi

  2. Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

    Fatemeh Namazi & Ali Mohammadi

Authors
  1. Masoumeh Honarmand
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  2. Fatemeh Namazi
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  3. Ali Mohammadi
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  4. Saeed Nazifi
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Corresponding author

Correspondence to Fatemeh Namazi.

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Animal ethics

The current experimental study was done based on the ethical and technical regulations of the state internal ethics committee of Shiraz University, Shiraz, Iran. Furthermore, the advices by European Council Directive (86/609/EC) of November 24, 1986, on animal rights for scientific purposes, were considered.

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Honarmand, M., Namazi, F., Mohammadi, A. et al. Can cannabidiol inhibit angiogenesis in colon cancer?. Comp Clin Pathol 28, 165–172 (2019). https://doi.org/10.1007/s00580-018-2810-6

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