Abstract 1898: The effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on the tumorigenesis of lung squamous cell carcinoma

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Lung cancer accounts for the majority of cancer mortality, research in this disease predominatly focuses on adenocarcinoma, which accounts for 32% of all lung cancers. Lung squamous cell carcinoma (SCC) accounts for 30% of lung cancer cases, thus the need for further knowledge about prevention and treatment is crucial. Unlike other major cancers, preventive agents and screening guidelines have not been established for lung cancer. The fact that calcitriol has the ability to induce cell cycle arrest, apoptosis and differentiation without toxicity, makes calcitriol an attractive potential agent for chemoprevention of lung cancer. In addition, vitamin D deficiency is associated strongly with the increased risk and poor prognosis of lung cancer. We are investigating the effects of calcitriol in cell lines, clinical samples and an animal model of lung SCC. We hypothesized that calcitriol will decrease the progression of lung cancer and enhance efficacy of calcitriol in lung cancer. The effects of calcitriol are mediated by vitamin D receptor (VDR) binding and activation of vitamin D responsive target genes, which are involved in the regulation of cell cycle arrest, differentiation and apoptosis. Nuclear localization of VDR is increased in malignant lung tissue, suggesting it may be a good target for cancer therapy. To examine anti-tumor effects, studies were carried out in three human cell lines, non-malignant human bronchial epithelium (BEAS-2B), a lung squamous cell carcinoma (128-88T) and lung adenocarcinoma (A549). Western blot analysis demostrated that the three cell lines have intact VDR signaling. Cell treated with 100 nM calcitriol for 24 hour resulted in VDR induction and nuclear translocation. Additionally, A549 and 128-88T cells demonstrated a 30% growth inhbition following treatment with 100 nM calcitriol for 48 hours. To further understand the effects of calcitriol on the development and progression of lung SCC, we used a carcinogen-induced in vivo model. SWR/J mice are treated topically with the carcinogen, N-nitroso-tri-chloroethylurea (NTCU), continually throughout each experiment. The development of lung SCC in the NTCU-incuduced mouse model closely resembles the formation of human lung SCC beginging with hyperplasia followed by squamous metaplasia, dysplasia, carcinoma in situ, and microinvasive carcinoma. These studies examine the effects of calcitriol on disease progression by evaluating molecular and morphological changes. NTCU-induced mice will be treated with calcitriol for 1 week and VDR activity and known transcrional targets (CYP24A1, p21, BCL-2, & VEGF) will be assessed. We will also examine how long-term (10 to 50 weeks) calcitriol treatments will affect the formation and growth of lung SCC in this model. The goal of the project is to determine the preventive effects of calcitriol on lung SCC. Supported by NIH/NCI R01-CA-067267. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1898.