alitretinoin and Carcinoma--Small-Cell

Lung cancer is the leading cause of cancer death worldwide. A diet rich in fruit and vegetables has been shown to reduce the lung cancer risk. However, clinical trials with beta-carotene and retinoids have disappointed, resulted in increased mortality from lung cancer and cardiovascular disease.. We have investigated the effects of the two major retinol metabolites, 9-cis-retinoic acid (9-Cis-RA), and 13-cis-retinoic acid (13-Cis-RA), on cell proliferation (MTT assays), intracellular cAMP (cAMP immunoassays), PKA activation (non-radioactive PKA activation assays), and ERK1/2 phosphorylation (Western blots) in immortalized human small airway epithelial cells, HPL1D, a human lung adenocarcinoma cell line, NCI-H322, immortalized human bronchial epithelial cells, BEAS-2B, and in the human small cell lung carcinoma cell line, NCI-H69.. Both retinoids increased intracellular cAMP and PKA activation in all cell lines. In BEAS-2B and NCI-H69 cells, the stimulation of cAMP/PKA reduced the phosphorylation of ERK1/2 and inhibited cell proliferation whereas phosphorylation of ERK1/2 and cell proliferation were increased in HPL1D and NCI-H322 cells.. Our data have identified a novel mechanism of action of 9-Cis-RA and 13-Cis-RA: activation of PKA in response to increased cAMP. The observed stimulation of cAMP/PKA may inhibit the development of small cell lung carcinoma and other tumors derived from large airway epithelia whereas it may selectively promote the development of lung tumors derived from small airway epithelial cells, such as adenocarcinoma.

Topics: Adenocarcinoma; Alitretinoin; Blotting, Western; Bronchi; Carcinoma, Small Cell; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Activation; Epithelial Cells; Humans; Immunoassay; Isotretinoin; Lung Neoplasms; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Respiratory Mucosa; Signal Transduction; Tretinoin; Tumor Cells, Cultured

The two stereoisomers of retinoic acid (RA), all-trans and 9-cis-RA, are regulators of cell proliferation, differentiation and apoptosis. In this study, the aim was to evaluate the effects of all-trans-and 9-cis-RA on cell growth, proliferation, and on the induction of apoptosis in the human small cell lung carcinoma (SCLC) cell lines NCI-H82 and NCI-H209. The application of various concentrations of all-trans and 9-cis-RA were able to inhibit cell growth and proliferation. Moreover, 3H-thymidine incorporation was inhibited and the number of viable cells decreased, suggesting that all-trans-RA and 9-cis-RA can inhibit cell proliferation in a dose dependent manner. Morphological examinations (light, electron and fluorescence microscopy) demonstrated that both retinoids had profound effects on the induction of apoptosis. Our investigation also showed that, compared to all-trans-RA, 9-cis-RA is a stronger inducer for the inhibition of cell growth and proliferation and that it is more effective in the induction of apoptosis in small cell lung carcinoma cells in culture.

Topics: Alitretinoin; Apoptosis; Carcinoma, Small Cell; Cell Differentiation; Cell Division; Cell Survival; Humans; Microscopy, Electron; Microscopy, Fluorescence; Thymidine; Tretinoin; Tumor Cells, Cultured

The effects of a combination of vitamin D3 [1,25(OH)2D3] and retinoic acid (RA) on proliferation, differentiation, and apoptosis of the human small cell lung carcinoma (SCLC) cell lines NCI-H82 and NCI-H209 were evaluated. Cell proliferation was inhibited by 1,25(OH)2D3 and RA alone. The combination of 1,25(OH)2D3 and the cis form of retinoic acid resulted in an additive decrease in cell proliferation and the induction of apoptosis in various concentrations. Moreover, 3H-thymidine incorporation was inhibited and the number of viable cells was decreased. The characteristics of the apoptotic cells were examined and confirmed by morphologic analysis, light and electron microscopy, and fluorescence detection. It was concluded that 1,25(OH)2D3 and RA exert additive effects on the inhibition of proliferation and the induction of apoptosis in both the NCI-H82 and the NCI-H209 SCLC cell lines. This finding has important implications for the use of retinoids and 1,25(OH)2D3 in cancer prevention and in the therapy of small cell lung carcinoma.

Topics: Alitretinoin; Apoptosis; Carcinoma, Small Cell; Cell Differentiation; Cell Division; Cholecalciferol; Drug Synergism; Drug Therapy, Combination; Humans; Lung Neoplasms; Microscopy, Electron; Stereoisomerism; Thymidine; Tretinoin; Tumor Cells, Cultured

Topics: Alitretinoin; Antineoplastic Agents; Carcinoma, Small Cell; Gene Deletion; Humans; Loss of Heterozygosity; Lung Neoplasms; Mutation; Neoplasms, Second Primary; Smoking; Survival Analysis; Tretinoin; Vitamin A Deficiency