Experimental study of the inhibitory effect of indomethacin on the growth and angiogenesis of human colon cancer xenografts

Abstract

Abstract: Objective To evaluate the efficacy of nonsteroidal anti-inflammatory drug indomethacin on tumor growth and microvessel angiogenesis of human colon cancer xenografts in nude mice. Methods Human colorectal cancer HCT116 cells were inoculated subcutaneously into BALB/c-nu/nu mice. After daily treatment with oral indomethacin for 4 weeks (3 mg·kg^-1·d^-1), the mice were sacrificed by cervical dislocation, and immunohistochemical staining was employed to determine microvessel density (MVD) and expression of vascular endothelial growth factors (VEGF) in the tumor tissues. Results Growth of HCT116 tumor was significantly suppressed by indomethacin. The tumor volume (mm³) was 458.89±32.07 in the treated group versus 828.21±31.59 in the control group (P<0.05). The MVDs of the treated and control groups were 19.50±5.32 and 37.40±4.93 respectively (P<0.001), and VEGF expressions were 1.19±0.17 and 1.90±0.48 (P<0.01), respectively. MVD and VEGF expression in the treated tumor tissue declined noticeably as compared with the controls. There was a positive correlation between the decrease of VEGF expression and that of MVD (r_s=0.714, P<0.05). No obvious toxicity was observed in nude mice. Conclusion Indomethacin can inhibit the growth of transplanted human colorectal HCT116 tumor in association with a significant reduction in angiogenesis, which may be achieved through inhibition of VEGF.

CLC Number:

WANG Hong-mei, ZHANG Gui-ying. Experimental study of the inhibitory effect of indomethacin on the growth and angiogenesis of human colon cancer xenografts[J]. Journal of Southern Medical University, 2004, 24(02): 184-187.

References

[1] Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor factor responsible or angiogenesis[J]. J Exp Med, 1971, 133(2): 275-88.
[2] Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors[J]. Cancer Res,2000, 60(5): 1306-11.
[3] Sawaoka H, Tsuji S, Tsujii M, et al. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo[J]. Lab Invest,1999, 79(12): 1469-77.
[4] Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis andmetastasis: correlation in invasive breast carcinoma[J]. New Eng J Med, 1991, 324(1): 1-8
[5] Breasalier RS, HO SB, Schoeppner HL, et al. Enhanced sialylation of mucin-associated carbohydrate structures in human colon cancer metastasis[J]. Gastroenterology, 1996, 110(5): 1354-67.
[6] Frelin C, Ladoux A, D’angelo G. Vascular endothelial growth factors and angiogenesis[J]. Ann Endocrinol (Paris), 2000, 61(1): 70-4.
[7] Gerwins P, Skoldenberg E, Claesson WL, et al. Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis[J]. Crit Rev Oncol Hematol, 2000,34(3): 185-94.
[8] Tsujii M, Kawano S, Tsuji S, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells[J]. Cell, 1998, 93(5): 705-16.
[9] Jones MK, Wang H, Peskar BM, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing[J]. Nat Med,1999, 5(12): 1418-23.
[10] Ristimkai A, Honkanen N, Jankala H, et al. Expression of cyclooxygenase-2 in human gastric carcinoma[J]. Cancer Res, 1997, 57 (7):1276-80.
[11] Pai R, Szabo IL, Kawanaka H, et al. Indomethacin inhibits endothelial cell proliferation by suppressing cell cycle proteins and PRB phosphorylation. A key to its anti-angioganic action[J]? Mol Cell Biol Res Commun, 2001, 4(1): 111-6.
[12] Kawai N, Tsujii M, Tsuji S. Cyclooxygenases and colon cancer[J].Prostaglandins Other Lipid Mediat, 2002, 68-69: 187-96.
[13] Leahy KM, Ornberg RL, Wang Y, et al. Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelisl cells in vivo[J]. Cancer Res, 2002, 62(3):625-31.
[14] Tarnawski AS, Jones MK. Inhibition of angiogenesis by NSAIDs:molecular mechanisms and clinical implications[J]. J Mol Med,2003, 81(10): 627-36.
[15] Ma L, del Soldato D, Wallace JL. Divergent effects of new cyclooxygenase inhibitors on gastriculcer healing: shifting the angiogenic balance[J]. Proc Natl Acad Sci USA, 2002, 99(20): 13243-7.