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. Non-invasive magnetic resonance imaging (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 down regulation 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.

Impact of Age on Disease Progression and Microenvironment in Oral Cancer

“…We utilized noninvasive T2-weighted MRI (T2W-MRI) to longitudinally monitor the effects of 4NQO exposure in old and young C57BL/6 mice. In a previous study, T2W-MRI of 6- to 8-wk-old mice that were not exposed to the carcinogen 4NQO did not show any evidence of oral or extraoral neoplasms (Bothwell et al 2015). Similarly, MRI examination performed on naïve mice of different ages without intervention (i.e., 4NQO exposure) did not show any evidence of oral neoplasms (Appendix Figs.…”

“…The carcinogen 4NQO was dissolved in propylene glycol at 4 mg/mL and diluted in autoclaved water to a final concentration of 100 μg/mL (Bothwell et al 2015). Young and old C57BL/6 mice were exposed to 4NQO in drinking water for 16 wk (Fig.…”

Development and Radiation Response Assessment in A Novel Syngeneic Mouse Model of Tongue Cancer: 2D Culture, 3D Organoids and Orthotopic Allografts

“…4NQO is a water-soluble chemical that leads to the malignant transformation and development of invasive cancer through intracellular oxidative stress and the formation of DNA adducts [14,15]. Studies by us and others have shown that 4NQO-induced tumors share histopathologic and molecular features of human OSCC and the model can serve as a useful platform to investigate the activity of chemopreventive agents against the spectrum of oral carcinogenesis [16][17][18]. Although disease progression in this model can be accelerated by simultaneous treatment with tumor promoters (e.g., ethanol), the requirement of chronic administration of the carcinogen (16-26 weeks) limits the widespread use of this model for therapeutic studies [19].…”

Effects of 1,25(OH)2D3 on Cancer Cells and Potential Applications in Combination with Established and Putative Anti-Cancer Agents

“…Similarly, Lainey et al [ 39 ] showed that either of the aforementioned EGFR inhibitors, together with 1,25(OH) 2 D 3 , induces markers and processes associated with differentiation, such as CD11b and CD14 expression, cell cycle arrest, apoptosis, and NADPH oxidase activity. Moreover, a recent study investigating the potential use of erlotinib together with 1,25(OH) 2 D 3 in head and neck squamous cell carcinoma utilized in vivo models to demonstrate augmented reduction of tumor growth in the combination regimen compared to single drug treatments [ 40 ]. Further analyses illustrated that this combination reduces phosphorylation of Akt (S473) and EGFR (Y1092) [ 40 ].…”

“…Moreover, a recent study investigating the potential use of erlotinib together with 1,25(OH) 2 D 3 in head and neck squamous cell carcinoma utilized in vivo models to demonstrate augmented reduction of tumor growth in the combination regimen compared to single drug treatments [ 40 ]. Further analyses illustrated that this combination reduces phosphorylation of Akt (S473) and EGFR (Y1092) [ 40 ].…”