Eugenol induces apoptosis and inhibits invasion and angiogenesis in a rat model of gastric carcinogenesis induced by MNNG

• Published in: Life sciences (1973) 2010-06, Vol.86 (25), p.936-941
• Main Authors: Manikandan, Palrasu, Murugan, Ramalingam Senthil, Priyadarsini, Ramamurthi Vidya, Vinothini, Govindarajah, Nagini, Siddavaram
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis; Apoptosis - drug effects; Blotting, Western; Chemoprevention; Densitometry; Disease Models, Animal; Eugenol; Eugenol - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Immunohistochemistry; Invasion; Male; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Methylnitronitrosoguanidine; MNNG; Neoplasm Invasiveness; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms - blood supply; Stomach Neoplasms - chemically induced; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2010.04.010

Combining apoptosis induction with anti-invasive and anti-angiogenic treatment is gaining increasing attention as a promising strategy for cancer chemoprevention. In the present study, eugenol (4-allyl-2-methoxyphenol) was evaluated for its chemopreventive effects on N-methyl-N ′-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in Wistar rats by analyzing markers of apoptosis, invasion and angiogenesis. The expressions of markers of apoptosis (Bcl-2, Bcl-xL, Bax, Apaf-1, cytochrome C, caspase-9, caspase-3 and poly(ADP-ribose)polymerase; PARP), invasion (matrix metalloproteinase-2; MMP-2, matrix metalloproteinase-9; MMP-9, reversion-inducing cysteine rich protein with Kazal motifs; RECK and tissue inhibitors of metalloproteinase-2; TIMP-2) and angiogenesis (vascular endothelial growth factor; VEGF and VEGF receptor1; VEGFR1) in stomach tissue of experimental and control animals were measured by gelatin zymogram, immunohistochemical, Western blot and RT-PCR analysis. Rats administered MNNG developed gastric carcinomas that displayed apoptosis avoidance coupled to upregulation of pro-invasive and angiogenic factors. Administration of eugenol induced apoptosis via the mitochondrial pathway by modulating the Bcl-2 family proteins, Apaf-1, cytochrome C, and caspases and inhibiting invasion, and angiogenesis as evidenced by changes in the activities of MMPs and the expression of MMP-2 and -9, VEGF, VEGFR1, TIMP-2 and RECK. Phytochemicals such as eugenol that are capable of manipulating the equilibrium between pro- and anti-apoptotic proteins as well as the delicate balance between stimulators and inhibitors of invasion and angiogenesis are attractive candidates for preventing tumour progression.