title: Impact of Short-term 1,25-Dihydroxyvitamin D3 on the Chemopreventive Efficacy of Erlotinib against Oral Cancer.
abstract: Activation of the epidermal growth factor receptor (EGFR) pathway is an early event in head and neck carcinogenesis. As a result, targeting EGFR for chemoprevention of head and neck squamous cell carcinomas (HNSCC) has received considerable attention. In the present study, we examined the impact of 1,25(OH)2D3, the active metabolite of the nutritional supplement vitamin D on the chemopreventive efficacy of the EGFR inhibitor, erlotinib, against HNSCC. Experimental studies were conducted in patient-derived xenografts (PDX) and the 4-nitroquinoline-1-oxide (4NQO) carcinogen-induced model of HNSCC. Short-term treatment (4 weeks) of PDX-bearing mice with 1,25(OH)2D3 and erlotinib resulted in significant inhibition of tumor growth. Noninvasive MRI enabled longitudinal monitoring of disease progression in the 4NQO model with 100% of control animals showing evidence of neoplastic lesions by 24 weeks. Among the experimental groups, animals treated with the combination regimen showed the greatest reduction in tumor incidence and volume (P < 0.05). Combination treatment was well tolerated and was not associated with any significant change in body weight. Histopathologic assessment revealed a significant reduction in the degree of dysplasia with combination treatment. Immunoblot analysis of whole tongue extracts showed downregulation of phospho-EGFR and phospho-Akt with the combination regimen. These results highlight the potential of 1,25(OH)2D3 to augment the efficacy of erlotinib against HNSCC. Further optimization of schedule and sequence of this combination regimen along with investigation into the activity of less calcemic analogues or dietary vitamin D is essential to fully realize the potential of this approach.
authors.affiliation: Department of Pharmacology and Therapeutics.
authors.forename: Katelyn D
authors.initials: KD
authors.lastname: Bothwell
authors.affiliation: Department of Pharmacology and Therapeutics.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Shaurova
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Mihai
authors.initials: M
authors.lastname: Merzianu
authors.affiliation: Roswell Park-Mazumdar Shaw Cancer Center Collaborative Research Program.
authors.forename: Amritha
authors.initials: A
authors.lastname: Suresh
authors.affiliation: Department of Oral Medicine and Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Moni A
authors.initials: MA
authors.lastname: Kuriakose
authors.affiliation: Department of Pharmacology and Therapeutics.
authors.forename: Candace S
authors.initials: CS
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology and Therapeutics.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hershberger
authors.affiliation: Department of Pharmacology and Therapeutics. Roswell Park-Mazumdar Shaw Cancer Center Collaborative Research Program. Department of Oral Medicine and Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York. Mukund.Seshadri@roswellpark.org.
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002117:Calcitriol / Q000008:administration & dosage*; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000517:prevention & control; D018450:Disease Progression; D015536:Down-Regulation; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006258:Head and Neck Neoplasms / Q000517:prevention & control; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D015363:Quinolones
chemical_list: C120195:4-nitroquinolone-1-oxide; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D015363:Quinolones; D015112:4-Nitroquinoline-1-oxide; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D002117:Calcitriol