Angiostatic Properties of Sulindac and Celecoxib in the Experimentally Induced Inflammatory Colorectal Cancer

作者：Vaish Vivek; Piplani Honit; Rana Chandan; Sanyal Sankar Nath^*

来源：Cell Biochemistry and Biophysics, 2013, 66(2): 205-227.

DOI：10.1007/s12013-012-9469-4

• Angiogenesis
• Chronic inflammation
• Colorectal cancer
• Cyclooxygenase-2
• Gelatin zymography
• Matix metalloproteinases
• Molecular docking

Initiation of various cancers has been observed to be regulated via a prolonged inflammatory state in the tissues. However, molecular role of such a localized inflammation is not clear in the advanced stages of colorectal cancer. In this study, we have elaborated the role of various pro- and anti-inflammatory cytokines, transcription, and angiogenic factors in the progression of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced late phage colorectal cancer and also observed the chemopreventive role of the two non-steroidal anti-inflammatory drugs (NSAIDs), viz., Sulindac and Celecoxib. Carcinogenic changes were observed with morphological and histopathological studies, whereas mRNA and protein regulations of various biomolecules were identified via RT- or qRT-PCR, western blot and immunofluorescence analysis, respectively. Activity of inducible nitric oxide (NO) and cyclooxygenase-2 enzymes were analyzed using standard NO assay and prostaglandin E-2 immunoassay, whereas activities of matrix metalloproteinases (MMP-2 and-9) were identified by gelatin zymography. Flowcytometry was performed for the relative quantification of the apoptotic events. Molecular docking studies of Sulindac and Celecoxib were also performed with different target proteins to observe their putative mechanisms of action. As a result, we found that DMH-treated animals were having over-expression of various pro-inflammatory cytokines (IL-1 beta, IL-2, and IFN gamma), aberrant nuclear localization of activated cell survival transcription factors (NF-kappa B and Stat3) along with the increased incidence of activated angiogenic factors (MMP-2 and MMP-9) suggesting a marked role of inflammation in the tumor progression. However, NSAIDs co-administration has significantly reduced the angiogenic potential of the growing neoplasm.

• 出版日期2013-6