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Topical polyethylene glycol as a novel chemopreventive agent for oral cancer via targeting of epidermal growth factor response.

Wali RK, Kunte DP, De La Cruz M, Tiwari AK, Brasky J, Weber CR, Gibson TP, Patel A, Savkovic SD, Brockstein BE, Roy HK - PLoS ONE (2012)

Bottom Line: 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.In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, NorthShore University Healthsystem, Evanston, Illinois, United States of America. rwali@northshore.org

ABSTRACT
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 p21(cip1/waf1). In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis.

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Effect of PEG-8000 on tongue mucosal EGFR and cyclin D1 expression in 4 NQO-treated rats –The tongue sections were subjected to immunohistochemical analyses to assess changes in EGFR and Cyclin D1 expressions.As shown (left Panel - Figure 3A and 3B), baseline EGFR expression in the tongue mucosa of 4NQO-rats was higher than that of control rats (p<0.00001). Topical application of PEG however, caused a significant decline in the expression of EGFR (p<0.005). Furthermore, topical PEG application to 4-NQO rats caused similar effects on the expression of Cyclin D1, one of the downstream effectors of EGFR (right Panel - Figure 3A and 3B).
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pone-0038047-g003: Effect of PEG-8000 on tongue mucosal EGFR and cyclin D1 expression in 4 NQO-treated rats –The tongue sections were subjected to immunohistochemical analyses to assess changes in EGFR and Cyclin D1 expressions.As shown (left Panel - Figure 3A and 3B), baseline EGFR expression in the tongue mucosa of 4NQO-rats was higher than that of control rats (p<0.00001). Topical application of PEG however, caused a significant decline in the expression of EGFR (p<0.005). Furthermore, topical PEG application to 4-NQO rats caused similar effects on the expression of Cyclin D1, one of the downstream effectors of EGFR (right Panel - Figure 3A and 3B).

Mentions: EGFR overexpression in the premalignant head and neck lesions is correlated with the increased risk of progression to HNSCC and poor survival [19], [20]. Modulating EGFR expression can therefore serve as the key element of a chemopreventive strategy. Several groups, including ours have previously shown that anti-proliferative and chemopreventive effects of PEG against colorectal carcinogenesis are EGFR-mediated, as administration of PEG-gavages in carcinogen treated rats significantly reduced proliferation in colonic mucosa through downregulation of EGFR expression [13]. We therefore, investigated if a similar mechanism was implicated in the chemopreventive actions of topical PEG-8000 against HNSCC. The tongue sections were formalin fixed and examined by immunostaining to assess changes in the expression levels of EGFR. As shown in Figure 3A and B, topical application of PEG-8000 significantly lowered the intensity as well as the number of areas overexpressing EGFR in 4NQO-treated rats where baseline EGFR expression was much higher than the tongue/oral mucosa of healthy control rats. This implicates downregulation of EGFR as one of the potential mechanisms for PEG-induced chemoprevention of HNSCC. We further demonstrated that PEG significantly reduced the expression of Cyclin D1, a downstream effector of EGFR that is overexpressed in HNSCC [21] and involved in causing resistance to therapeutic drugs such as cisplatin [22] and gefitinib [23].


Topical polyethylene glycol as a novel chemopreventive agent for oral cancer via targeting of epidermal growth factor response.

Wali RK, Kunte DP, De La Cruz M, Tiwari AK, Brasky J, Weber CR, Gibson TP, Patel A, Savkovic SD, Brockstein BE, Roy HK - PLoS ONE (2012)

Effect of PEG-8000 on tongue mucosal EGFR and cyclin D1 expression in 4 NQO-treated rats –The tongue sections were subjected to immunohistochemical analyses to assess changes in EGFR and Cyclin D1 expressions.As shown (left Panel - Figure 3A and 3B), baseline EGFR expression in the tongue mucosa of 4NQO-rats was higher than that of control rats (p<0.00001). Topical application of PEG however, caused a significant decline in the expression of EGFR (p<0.005). Furthermore, topical PEG application to 4-NQO rats caused similar effects on the expression of Cyclin D1, one of the downstream effectors of EGFR (right Panel - Figure 3A and 3B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366973&req=5

pone-0038047-g003: Effect of PEG-8000 on tongue mucosal EGFR and cyclin D1 expression in 4 NQO-treated rats –The tongue sections were subjected to immunohistochemical analyses to assess changes in EGFR and Cyclin D1 expressions.As shown (left Panel - Figure 3A and 3B), baseline EGFR expression in the tongue mucosa of 4NQO-rats was higher than that of control rats (p<0.00001). Topical application of PEG however, caused a significant decline in the expression of EGFR (p<0.005). Furthermore, topical PEG application to 4-NQO rats caused similar effects on the expression of Cyclin D1, one of the downstream effectors of EGFR (right Panel - Figure 3A and 3B).
Mentions: EGFR overexpression in the premalignant head and neck lesions is correlated with the increased risk of progression to HNSCC and poor survival [19], [20]. Modulating EGFR expression can therefore serve as the key element of a chemopreventive strategy. Several groups, including ours have previously shown that anti-proliferative and chemopreventive effects of PEG against colorectal carcinogenesis are EGFR-mediated, as administration of PEG-gavages in carcinogen treated rats significantly reduced proliferation in colonic mucosa through downregulation of EGFR expression [13]. We therefore, investigated if a similar mechanism was implicated in the chemopreventive actions of topical PEG-8000 against HNSCC. The tongue sections were formalin fixed and examined by immunostaining to assess changes in the expression levels of EGFR. As shown in Figure 3A and B, topical application of PEG-8000 significantly lowered the intensity as well as the number of areas overexpressing EGFR in 4NQO-treated rats where baseline EGFR expression was much higher than the tongue/oral mucosa of healthy control rats. This implicates downregulation of EGFR as one of the potential mechanisms for PEG-induced chemoprevention of HNSCC. We further demonstrated that PEG significantly reduced the expression of Cyclin D1, a downstream effector of EGFR that is overexpressed in HNSCC [21] and involved in causing resistance to therapeutic drugs such as cisplatin [22] and gefitinib [23].

Bottom Line: 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.In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, NorthShore University Healthsystem, Evanston, Illinois, United States of America. rwali@northshore.org

ABSTRACT
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 p21(cip1/waf1). In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis.

Show MeSH
Related in: MedlinePlus