Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro

• Published in: European journal of pharmacology 2010-12, Vol.649 (1), p.64-73
• Main Authors: Hamsa, T.P., Kuttan, Girija
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Angiogenic Proteins - blood; Angiogenic Proteins - genetics; Angiogenic Proteins - metabolism; Animals; Anti-angiogenesis; Antineoplastic Agents, Phytogenic - pharmacology; B16F-10 melanoma; Biological and medical sciences; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Dermatology; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Harmine; Harmine - pharmacology; Humans; In Vitro Techniques; Inflammation Mediators - blood; Inflammation Mediators - metabolism; Male; Medical sciences; Melanoma, Experimental - blood supply; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Mice; Mice, Inbred C57BL; Microvessels - drug effects; Neovascularization, Pathologic - blood; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - prevention & control; Pharmacology. Drug treatments; Pro-inflammatory cytokine; Rats; RNA, Messenger - metabolism; Transcription factor; Tumors of the skin and soft tissue. Premalignant lesions; Vascular Endothelial Growth Factors - blood; Vascular Endothelial Growth Factors - genetics; Vascular Endothelial Growth Factors - metabolism; VEGF
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2010.09.010

Harmine is a beta-carboline alkaloid present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In this study, we demonstrated the anti-angiogenic activity of harmine using in vivo and in vitro assay systems. In vivo anti-angiogenic activity was studied using B16F-10 melanoma cells which induced capillary formation in C57BL/6 mice. Intraperitoneal administration of harmine at 10 mg/kg body weight significantly decreased tumour directed capillary formation. A drastic elevation in serum pro-angiogenic factors such as vascular endothelial growth factor (VEGF), nitric oxide (NO) and pro-inflammatory cytokines in angiogenesis induced animals was significantly decreased by harmine treatment. At the same time harmine increased anti-tumour factors like interleukin-2 (IL-2) and tissue inhibitor metalloprotease (TIMP). Moreover nuclear factor (NF)-κB and other transcription factors like CREB, ATF-2 involved in tumour development and angiogenesis were also inhibited by harmine. Various in vitro assays also supported the anti-angiogenic activity of harmine. It reduced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). Direct treatment of the harmine also inhibited microvessel outgrowth from the rat aortic ring. Production of other factors by tumour cells which are involved in angiogenesis like cyclooxygenase (COX-2), inducible nitric oxide synthase (iNOS) and matrix metalloproteases (MMPs) were also decrease by the treatment with harmine. Our data suggest that harmine may be a strong angiogenic inhibitor with the ability to decrease the proliferation of vascular endothelial cells and to reduce expression of various pro-angiogenic factors.