alitretinoin and Carcinoma

The prognosis of advanced colorectal carcinoma (CC) is poor. Established chemotherapy shows only limited efficacy but significant side effects. We investigated how far a combination of tamoxifen (TAM), 9-cis-retinoic acid (CRA) and the fluoroquinolone ciprofloxacin (CIP) synergize to inhibit proliferation and promote apoptosis of CC cells in vitro. The CC cell lines LOVO, CC-531 and SW-403 were incubated with TAM, CRA and CIP (10(minus;4)-10(minus;6) M) as single agents and in combination. Cell proliferation was assessed by bromodeoxyuridin incorporation. Apoptosis was quantified immunohistochemically and by FACS analysis after staining with propidium iodide. Changes in the expression of caspase 3, bax, bcl-2 and p21cip/waf were assessed by quantitative Western blotting. CRA and TAM monotherapy was moderately effective. Their combination enhanced apoptosis from 60% to more than 80% in all cell types. Apoptosis was paralleled by inhibition of proliferation and further potentiated by addition of CIP. The combination effectively up-regulated caspase 3 and bax and down-regulated bcl-2 and p21cip/waf. Combinations of biomodulaters act synergistically to inhibit proliferation and promote apoptosis in CC cells. Due to their known safety profile, this justifies clinical trials for colorectal cancer using combinations of these biological response modifiers.

Topics: Alitretinoin; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Bromodeoxyuridine; Carcinoma; Caspase 3; Caspases; Cell Division; Cell Line, Tumor; Cell Separation; Ciprofloxacin; Colonic Neoplasms; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunohistochemistry; Indicators and Reagents; Kinetics; Prognosis; Propidium; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tamoxifen; Time Factors; Tretinoin

Peroxisome proliferator-activated receptor gamma (PPARgamma) forms a heterodimeric DNA-binding complex with the retinoid X receptor (RXR) and regulates the transcription of its target genes. Activation of PPARgamma has been shown to induce G1 arrest and to inhibit cell growth of human pancreatic carcinoma cell lines. The purpose of the present study was to examine the effect of ligand activation of PPARgamma and RXR on cell growth and on the expression of G1 cyclins in a pancreatic cancer cell line PANC-1, which expresses PPARgamma at high levels. Troglitazone, a specific ligand for PPARgamma, was found to cause a reduction in the growth rate and induced G1 cell cycle arrest and this effect was additive with that of 9-cis retinoic acid (9-cis RA), a ligand for RXR. Of the G1 cyclins tested, troglitazone specifically reduced the expression of cyclin D1 mRNA and the corresponding protein and this effect was also additive with 9-cis RA. These results suggest that the activation of PPARgamma together with RXR may be useful for the suppression of pancreatic cancer cell growth through the reduction in cyclin D1 levels.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Blotting, Northern; Blotting, Western; Carcinoma; Cell Division; Chromans; Cyclin D1; Dose-Response Relationship, Drug; Drug Synergism; G1 Phase; Humans; Pancreatic Neoplasms; Rats; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazoles; Thiazolidinediones; Transcription Factors; Transfection; Tretinoin; Troglitazone; Tumor Cells, Cultured