Role of cytokines and Jak3/Stat3 signaling in the 1,2-dimethylhydrazine dihydrochloride-induced rat model of colon carcinogenesis

Abstract

The molecular mechanisms by which colon cancer cells regulate the expression of various proinflammatory and anti-inflammatory cytokines and transcription factors resulting in tumor progression have not been well clarified. The present study thus explores the effect of cancer cell-derived cytokines and transcription factors on the chemoprevention of a rat model of early colon carcinogenesis. Elevated expression of proinflammatory cytokines [interleukin-1β (IL-1β), IL-2, interferon γ, and tumor necrosis factor-α] and the transcription factors [Janus kinase 3 (Jak3) and signal transducer and activator of transcription 3 (Stat3)] was found in the 1,2-dimethylhydrazine dihydrochloride (DMH) group; however, this elevated expression was reversed by the individual and combination treatment with piroxicam, a traditional nonsteroidal anti-inflammatory drug [inhibiting both cyclooxygenase-1 (COX-1) and COX-2] and c-phycocyanin, a cyanobacterium-derived biliprotein from Spirulina platensis (selective COX-2 inhibitor). In the DMH group, low expression of IL-4, an anti-inflammatory cytokine, was further observed with respect to the other groups. Expression of inducible nitric oxide synthase and nitric oxide/citrulline levels was also analyzed and was found to be elevated with DMH treatment. Increased apoptotic index and stimulated levels of Bcl-2-associated death promoter (Bad), a proapoptotic protein, were observed in piroxicam-treated and c-phycocyanin-treated rats. In-silico molecular docking of piroxicam as a ligand with several regulatory proteins was performed, indicating that, except inducible nitric oxide synthase, it effectively binds with COX-1, COX-2, Jak3, and Stat3. Piroxicam and c-phycocyanin perhaps showed chemopreventive properties by inhibiting proinflammatory cytokines and Jak3/Stat3 signaling while promoting apoptosis. In addition, a combination regimen was found to be more beneficial than monotherapy.

Agro‐Industrial Waste Based Phycocyanin Production from Oscillatoria sp. 50 A: daf‐16 Modulating Effect in Caenorhabditis elegans and p53 Dependent Apoptosis in HeLa cells

“…C‐PC has also been prospected for various medicinal applications like anti‐inflammatory drug in vitro in murine microglial cells BV‐2, where C‐PC protects BV‐2 cells from the pro‐inflammatory and cytotoxic effects of LPS, further it was also reported that a sufficient dose of oral administration of C‐PC may provide protection against neurodegenerative disorders, where microglial activation was the root of disease pathogenesis as in the case of Parkinsons disorder . C‐PC also sustains reports of cytotoxicity in vitro in various cell lines, like colon cancer, HT‐29 (colon) and A549 (lung adenocarcinoma) ,. In this study, C‐PC also showed a cytotoxic effect on HeLa cells with an IC 50 value of 77.60 ± 2.41 μg/ml as seen by MTT assay (Supplementary Figure S6).…”

Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer

“…Colonocytes were obtained from the freshly isolated colons by the method of Mouille et al 2004 as described earlier [16,18]. Trypan blue dye exclusion was performed each time for every group of isolated colonocytes, and the viability of cells observed *90 %.…”

“…Curcumin is also pharmacologically safe as it is a naturally occurring compound used as a foodcoloring agent and in traditional medicines to treat various diseases in Asian countries and also as carrier in nanomedicines [13,14]. There is increasing interest in the application that combination of cancer chemopreventive agents may produce considerably stronger protective effects against carcinogenesis than each chemopreventive agent could do so individually [15,16]. We had shown earlier that the combinatorial regimen of non-steroidal antiinflammatory drugs (NSAIDs) and natural compounds produced enhanced chemopreventive effects in early colon cancer than the administration of either agent alone [17,18].…”

C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment

“…The STAT family of proteins are transcription factors, known for their role as integrators of cytokine and growth factor-receptor signaling, which is required for cell growth, survival, differentiation, and motility [20-22]. Activated STAT3 has also been shown to be associated with increased expression of cytokines, growth factors, matrix metalloproteinases (MMPs), and angiogenic factors [23].…”