Colorectal cancer (CRC) ranks as the second leading cause of cancer deaths in the USA and thus highlighting the need for effective chemopreventive strategies. Several chemopreventive agents have shown promise in clinical studies;however, feasibility for population based CRC prevention has been hindered by insufficient efficacy or increased toxicity of number of these agents. Therefore, a safer and more potent agent is urgently needed. In this regard, work from a number of groups including ours, indicates that polyethylene glycol (PEG) is one of the most potent chemopreventive agents against both the azoxymethane (AOM)-treated rat and MIN mouse models of colon carcinogenesis. Moreover, PEG is widely used (over-the-counter) in clinical practice for the treatment of chronic constipation where it is remarkably safe. The critical issue for standardizing the effectiveness of a chemopreventive agent (nonsteroidals, etc) is the intra-individual variability. For PEG, the intra-individual variability may relate to its chemopreventive responsiveness as well as its effect on the bowel movement. The """"""""normal'bowel habits of Americans range from 3 per day to 3 per week and PEG can dramatically influence these routines. Moreover, since bowel habits will effect mucosal contact time, this may affect chemopreventive response. Thus, it is clear that a single dose of PEG may not be effective in all patients and therefore, needs to be calibrated for individual requirements. It is critical to find a biomarker of PEG responsiveness that would be extremely dependable and easily accessible. Our laboratory has been interested in exploring the mechanism of action of PEG We demonstrated that PEG inhibited cellular proliferation in vivo in the premalignant mucosa of AOM-treated rat as well as in vitro in colon cancer cells. Increased cellular proliferation is an important premalignant cellular event that can be detected in the uninvolved mucosa distant from the site of developing neoplastic lesions (field effect). We have previously proposed a paradigm where PEG inhibits transcriptional repressor Snail (upregulated in CRC) with a concomitant induction of E-cadherin, inhibition of 2-catenin signaling (vital in early carcinogenesis) leading to PEG's anti-proliferative effects. Furthermore, we have noted (preliminary data) that PEG decreases the expression of epidermal growth factor receptor (EGFR), a critical proto-oncogene in early colon carcinogenesis and known to regulate Snail. We speculate that EGFR is the proximate membrane target for PEG effect. The importance of EGFR is underscored by our observation that in cell culture, knocking down EGFR via shRNA resulted in marked diminution of PEG responsiveness and its inability to downregulate Snail. We therefore, hypothesize that EGFR levels in the uninvolved mucosa will be an accurate biomarker for PEG-mediated chemoprevention of colon carcinogenesis. Furthermore, tailoring PEG dosage to EGFR levels will be an optimal approach. We contemplate that PEG will affect both facets of chemoprevention: prevention of initiation of lesions as well as regression of established premalignant lesions (adenomas).
Principal Investigator Wali, Ramesh K Colonic carcinogenesis is a multistep process that gradually evolves through recurring changes in the genetic, biochemical and morphological features of the initiated colonic mucosa. Owing to its slow transition from initiation to tumor development, colonic carcinogenesis suitably fits the criterion for effective chemopreventive interventions. Insights into the molecular determinants of carcinogenesis have given rise to new and discrete targets for preventive interventions. These may include development of new markers of risk or preventive response that are likely to improve clinical outcomes and reduce public health burden of colorectal cancer (CRC). The dependability of these biomarkers largely depends not only on their versatility in validating cancer prognosis and degree of remission but also on how best they correlate with the onset of colonic pre- malignancy. For chemopreventive interventions to be efficient, in addition to use of proper biomarkers to quantify its success, there is constant need to develop or identify new safe and efficacious nutritional or pharmacological chemopreventive agents. Non-steroidal anti-inflammatory drugs (NSAIDS) have been successfully used against CRC but recent revelations regarding their short and long-term side-effects including GI ulcers and other cardio vascular toxicities have reduced their population wide acceptability. Chemoprevention is a result of use of natural or pharmacological agents that halt, reverse or slow carcinogenesis. These can effect by inducing protection against mutagens/carcinogens through inhibition of uptake, activation or apoptosis. Other agents can modulate signal transduction through modulation of growth factor receptor functional activity In pursue of identifying safe and novel potent agents, whose chemopreventive effects can be measured by responses in specific biochemical targets, our laboratory and others, suggest that a novel CRC chemopreventive agent, polyethylene glycol (PEG) may be a wonder agent. This is not only because of its very compelling anti-carcinogenic property but also for its well-tolerated safety profile. In this proposal we now want to study the mechanism of PEG-induced chemoprevention by studying its effect on target responses in premalignant colonic mucosa as well in colonic tumors. Based on our preliminary studies we suggest that PEG at the membrane level may be causing EGFR downregulation producing further changes in downstream signaling that ultimately deregulates transcriptional factor Snail. Since both EGFR has been shown to be very important in number of malignancies including colon cancer, we hypothesize that EGFR may be important signal transduction tool to predict and monitor PEG-induced chemoprevention and antiproliferation.
| Wali, Ramesh K; Kunte, Dhananjay P; De La Cruz, Mart et al. (2012) Topical polyethylene glycol as a novel chemopreventive agent for oral cancer via targeting of epidermal growth factor response. PLoS One 7:e38047 |
| Roy, Hemant K; Koetsier, Jennifer L; Tiwari, Ashish K et al. (2011) Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis. Int J Oncol 38:529-36 |
