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 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.
Department of Medicine, NorthShore University Healthsystem, Evanston, Illinois, United States of America. rwali@northshore.org
Ramesh K
RK
Wali
Dhananjay P
DP
Kunte
Mart
M
De La Cruz
Ashish K
AK
Tiwari
Jeffrey
J
Brasky
Christopher R
CR
Weber
Tina P
TP
Gibson
Amir
A
Patel
Suzana D
SD
Savkovic
Bruce E
BE
Brockstein
Hemant K
HK
Roy
D015112:4-Nitroquinoline-1-oxide; D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018890:Chemoprevention; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019938:Cyclin D1; D011092:Polyethylene Glycols; D015112:4-Nitroquinoline-1-oxide; D004815:Epidermal Growth Factor; D066246:ErbB Receptors