Topical Polyethylene Glycol as a Novel Chemopreventive Agent for Oral Cancer via Targeting of Epidermal Growth Factor Response

Head and neck squamous cell carcinoma (HNSCC) is a major cause of morbidity and mortality underscoring the need for safe and effective chemopreventive strategies. Targeting epidermal growth factor receptor (EGFR) is attractive in that it is an early critical event in HNSCC pathogenesis. However, current agents lack efficacy or have unacceptable toxicity. Several groups have demonstrated that the over-the-counter medication, polyethylene glycol (PEG) has remarkable chemopreventive efficacy against colon carcinogenesis. Importantly, we reported that this effect is mediated through EGFR internalization/degradation. In the current study, we investigated the chemopreventive efficacy of this agent against HNSCC, using both the well validated animal model 4-NQO (4-nitroquinoline 1-oxide) rat model and cell culture with the human HNSCC cell line SCC-25. We demonstrated that daily topical application of 10% PEG-8000 in the oral cavity (tongue and cavity wall) post 4NQO initiation resulted in a significant reduction in tumor burden (both, tumor size and tumors/tumor bearing rat) without any evidence of toxicity. Immunohistochemical studies depicted decreased proliferation (number of Ki67-positive cells) and reduced expression of EGFR and its downstream effectors cyclin D1 in the tongue mucosa of 4NQO-rats treated with PEG. We showed that EGFR was also markedly downregulated in SCC-25 cells by PEG-8000 with a concomitant induction of G1-S phase cell-cycle arrest, which was potentially mediated through upregulated p21cip1/waf1. In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis

The Use of Multivitamin/Multimineral Supplements:A Modified Delphi Consensus Panel Report

PURPOSE: Evidence supporting the use of dietary supplements, in particular, multivitamin/multimineral supplements (MVMS), has been mixed, complicating the ability of health care professionals to recommend their use. To clarify the role that MVMS can play in supporting human health, a series of consensus statements was developed based on expert opinion. METHODS: A panel of 14 international experts in nutritional science and health care was convened to develop consensus statements related to using MVMS in supporting optimal human health. The modified Delphi process included 2 rounds of remote voting and a final round of voting at a roundtable meeting where evidence summaries were presented and discussed. The level of agreement with each of 9 statements was rated on a 5-point Likert scale: agree strongly; agree with reservation; undecided; disagree; or disagree strongly. Consensus was predefined as ≥80% of the panel agreeing strongly or agreeing with reservation to a given statement. FINDINGS: Consensus was reached for all statements. The panel determined that MVMS can broadly improve micronutrient intakes when they contain at least the micronutrients that are consumed insufficiently or have limited bioavailability within a specified population. MVMS formulations may also be individualized according to age, sex, life cycle, and/or other selected characteristics. There are specific biological processes and health outcomes associated with deficient, inadequate, and adequate micronutrient levels. Adequate intake is necessary for normal biological functioning required for good health; in some instances, higher than recommended micronutrient intakes have the potential to provide additional health benefits. Meeting daily intakes established by dietary reference values should be an explicit public health goal for individuals and populations. Use of MVMS is one approach to ensure that adequate micronutrient needs are met in support of biological functions necessary to maintain health. Long-term use of MVMS not exceeding the upper limit of recommended intakes has been determined to be safe in healthy adults. There is insufficient evidence to indicate that MVMS are effective for the primary prevention of chronic medical conditions, including cardiovascular disease and cancer. However, for certain otherwise healthy subpopulations (eg, pregnant women, older adults) and some individuals with existing medical conditions who experience inadequacies in micronutrient intake, addressing inadequacies by using MVMS can provide health benefits. IMPLICATIONS: This consensus panel has described key issues related to the use of MVMS among individuals at risk of or presenting with inadequacies in micronutrient intake or biomarker status

Topical Polyethylene Glycol as a Novel Chemopreventive Agent for Oral Cancer via Targeting of Epidermal Growth Factor Response

Head and neck squamous cell carcinoma (HNSCC) is a major cause of morbidity and mortality underscoring the need for safe and effective chemopreventive strategies. Targeting epidermal growth factor receptor (EGFR) is attractive in that it is an early critical event in HNSCC pathogenesis. However, current agents lack efficacy or have unacceptable toxicity. Several groups have demonstrated that the over-the-counter medication, polyethylene glycol (PEG) has remarkable chemopreventive efficacy against colon carcinogenesis. Importantly, we reported that this effect is mediated through EGFR internalization/degradation. In the current study, we investigated the chemopreventive efficacy of this agent against HNSCC, using both the well validated animal model 4-NQO (4-nitroquinoline 1-oxide) rat model and cell culture with the human HNSCC cell line SCC-25. We demonstrated that daily topical application of 10% PEG-8000 in the oral cavity (tongue and cavity wall) post 4NQO initiation resulted in a significant reduction in tumor burden (both, tumor size and tumors/tumor bearing rat) without any evidence of toxicity. Immunohistochemical studies depicted decreased proliferation (number of Ki67-positive cells) and reduced expression of EGFR and its downstream effectors cyclin D1 in the tongue mucosa of 4NQO-rats treated with PEG. We showed that EGFR was also markedly downregulated in SCC-25 cells by PEG-8000 with a concomitant induction of G1-S phase cell-cycle arrest, which was potentially mediated through upregulated p21cip1/waf1. In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis.</p

Inhibition of cellular proliferation and induction of cell cycle arrest by PEG-8000 in SCC-25 cells- SCC-25 cells were treated with different concentrations of PEG-8000 for 24 h and then assayed for proliferation using standard WST-1 assay.

<p>As shown (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038047#pone-0038047-g004" target="_blank">Figure 4A</a>), there was a dose dependent decrease in the cell growth, with maximal decrease of 43% obtained at 10% PEG-8000. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038047#pone-0038047-g004" target="_blank">Figure 4B</a> shows a ∼50% decrease on the expression of proliferation marker PCNA by PEG. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038047#pone-0038047-g004" target="_blank">Figure 4C</a> shows the effect of PEG on cell cycle distribution. The 24 h PEG treated cells were stained with propidium iodide and analyzed by flow cytometry. PEG blocked cells in the S-phase (by 62%) and correspondingly increases the cells in G2-M phase (by 38%).</p

Effect of topical oral application of PEG-8000 on the initiation and progression of 4NQO-induced oral cancer –Fisher rats were provided 4NQO (20 ppm) in drinking water for 14 weeks before switching to regular water and randomizing into two groups.

<p>The first group received a daily (3–4 minute) topical application of 10% PEG-8000 via oral painting and the second group was sham painted (PEG-control group). This regimen was continued for 14 additional weeks before euthanization. The rats were euthanized after 14 weeks and the oral cavity subjected to macroscopic tumor assessment of total tumors (≥0.2 cm). As shown, 4NQO-treated rats developed multiple large tumors in the oral cavity mostly originating from tongue and few from the wall of the oral cavity. PEG reduced the overall tumor number (tumors/tumor bearing rat) (p = 0.05) and the growth of tumors (tumor volume) compared to their age-matched counterparts (p = 0.02). The tumor volume (size) was measured according to the formula width × length × height × π/6.</p