Background: We have previously reported the antineoplastic effects of a cannabinoid agonist in gastric cancer cells. Our aim was to evaluate this in a murine xenograft model. Methods: Animal models were created after injecting AGS gastric cancer cells subcutaneously into the flank of male BALB/c-nude mice. A cannabinoid agonist, WIN 55,212-2 (7 mg/kg body weight) or vehicle was injected around the tumor subcutaneously every 24 h for 14 days. Tumors were explanted for analysis. Results: Tumor volume decreased by 30% in the WIN 55,212-2-treated group compared to the group treated with vehicle (p < 0.05). Apoptotic cells were found more commonly in the WIN 55,212-2 treatment group than in the control on immunohistochemistry. Compared to the control, WIN 55,212-2 treatment significantly increased caspase-3 cleavage and decreased MMP-2, MMP-7 and MMP-9 protein levels significantly (all p < 0.05). VEGF-A protein level was not different between the 2 groups. Conclusion: WIN 55,212-2 has antineoplastic effect on the gastric cancers in in vivo model.

Keywords:
Cannabinoid receptor agonists, WIN 55,212-2, Stomach neoplasms, Matrix metalloproteinases
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
2.
Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE: Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;3:CD004064.
3.
Xiang XJ, Zhang L, Qiu F, Yu F, Zhan ZY, Feng M, Yan J, Zhao JG, Xiong JP: A phase II study of capecitabine plus oxaliplatin as first-line chemotherapy in elderly patients with advanced gastric cancer. Chemotherapy 2012;58:1-7.
4.
Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ: Cannabinoids for control of chemotherapy-induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21.
5.
Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA: Antineoplastic activity of cannabinoids. J Natl Cancer Inst 1975;55:597-602.
6.
Hermanson DJ, Marnett LJ: Cannabinoids, endocannabinoids, and cancer. Cancer Metastasis Rev 2011;30:599-612.
7.
Blazquez C, Carracedo A, Barrado L, Real PJ, Fernandez-Luna JL, Velasco G, Malumbres M, Guzman M: Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 2006;20:2633-2635.
8.
Jacobsson SO, Wallin T, Fowler CJ: Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther 2001;299:951-959.
9.
Blazquez C, Casanova ML, Planas A, Gomez Del Pulgar T, Villanueva C, Fernandez-Acenero MJ, Aragones J, Huffman JW, Jorcano JL, Guzman M: Inhibition of tumor angiogenesis by cannabinoids. FASEB J 2003;17:529-531.
10.
Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M: Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 2000;6:313-319.
11.
Salazar M, Carracedo A, Salanueva IJ, Hernandez-Tiedra S, Lorente M, Egia A, Vazquez P, Blazquez C, Torres S, Garcia S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, Gonzalez-Feria L, Iovanna JL, Guzman M, Boya P, Velasco G: Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 2009;119:1359-1372.
12.
Izzo AA, Camilleri M: Cannabinoids in intestinal inflammation and cancer. Pharmacol Res 2009;60:117-125.
13.
Xian XS, Park H, Cho YK, Lee IS, Kim SW, Choi MG, Chung IS, Han KH, Park JM: Effect of a synthetic cannabinoid agonist on the proliferation and invasion of gastric cancer cells. J Cell Biochem 2010;110:321-332.
14.
Park JM, Xian XS, Choi MG, Park H, Cho YK, Lee IS, Kim SW, Chung IS: Antiproliferative mechanism of a cannabinoid agonist by cell cycle arrest in human gastric cancer cells. J Cell Biochem 2011;112:1192-1205.
15.
Olea-Herrero N, Vara D, Malagarie-Cazenave S, Diaz-Laviada I: Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-methanandamide and JWH-015: involvement of CB2. Br J Cancer 2009;101:940-950.
16.
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.
17.
Qamri Z, Preet A, Nasser MW, Bass CE, Leone G, Barsky SH, Ganju RK: Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Mol Cancer Therap 2009;8:3117-3129.
18.
Cianchi F, Papucci L, Schiavone N, Lulli M, Magnelli L, Vinci MC, Messerini L, Manera C, Ronconi E, Romagnani P, Donnini M, Perigli G, Trallori G, Tanganelli E, Capaccioli S, Masini E: Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin Cancer Res 2008;14:7691-7700.
19.
DeMorrow S, Francis H, Gaudio E, Venter J, Franchitto A, Kopriva S, Onori P, Mancinelli R, Frampton G, Coufal M, Mitchell B, Vaculin B, Alpini G: The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical WNT signaling pathway. Am J Physiol Gastrointest Liver Physiol 2008;295:G1150-1158.
20.
Frampton G, Coufal M, Li H, Ramirez J, DeMorrow S: Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of notch signaling. Exp Cell Res 2010;316:1465-1478.
21.
Huang L, Ramirez JC, Frampton GA, Golden LE, Quinn MA, Pae HY, Horvat D, Liang LJ, DeMorrow S: Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor. Lab Invest 2011;91:1007-1017.
22.
Wang D, Wang H, Ning W, Backlund MG, Dey SK, DuBois RN: Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res 2008;68:6468-6476.
23.
Rundhaug JE: Matrix metalloproteinases and angiogenesis. J Cell Mol Med 2005;9:267-285.
24.
Nomura H, Fujimoto N, Seiki M, Mai M, Okada Y: Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A) in human gastric carcinomas. Int J Cancer 1996;69:9-16.
25.
Honda M, Mori M, Ueo H, Sugimachi K, Akiyoshi T: Matrix metalloproteinase-7 expression in gastric carcinoma. Gut 1996;39:444-448.
26.
Sier CF, Kubben FJ, Ganesh S, Heerding MM, Griffioen G, Hanemaaijer R, van Krieken JH, Lamers CB, Verspaget HW: Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer 1996;74:413-417.
27.
Curran S, Murray GI: Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer 2000;36:1621-1630.
28.
Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161-174.
29.
Monig SP, Baldus SE, Hennecken JK, Spiecker DB, Grass G, Schneider PM, Thiele J, Dienes HP, Holscher AH: Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma. Histopathology 2001;39:597-602.
30.
Chu D, Zhang Z, Li Y, Zheng J, Dong G, Wang W, Ji G: Matrix metalloproteinase-9 is associated with disease-free survival and overall survival in patients with gastric cancer. Int J Cancer 2011;129:887-895.
31.
Thapa D, Lee JS, Heo SW, Lee YR, Kang KW, Kwak MK, Choi HG, Kim JA: Novel hexahydrocannabinol analogs as potential anti-cancer agents inhibit cell proliferation and tumor angiogenesis. Eur J Pharmacol 2011;650:64-71.
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2013
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