retinamide and Lung-Neoplasms

To observe the effects of a novel all-trans retinoid acid (ATRA) derivative, N-(3-trifluoromethyl-phenyl)- retinamide (ATPR), on lung adenocarcinoma A549 cells and to explore the potential mechanism of ATPR inhibiting of A549 cell migration.. The cytotoxicity of ATRA and ATPR on A549 cells was assessed using MTT assay. Wound healing assays were used to analyze the influences of ATRA, ATPR, ML-7 (a highly selective inhibitor of myosin light chain kinase (MLCK)), PMA (an activator of MAPKs) and PD98059 (a selective inhibitor of ERK1/2) on the migration of A549 cells. Expression of MLCK and phosphorylation of myosin light chain (MLC) were assessed by Western blotting.. ATRA and ATPR inhibited the proliferation of A549 cells in a dose- and time-dependent manner, and the effect of ATPR was much more remarkable compared with ATRA. Relative migration rate and migration distance of A549 cells both decreased significantly after treatment with ATPR or ML-7. The effect on cell migration of PD98059 combining ATPR treatment was more notable than that of ATPR alone. Moreover, compared with control groups, the expression levels of MLCK and phosphorylated MLC in A549 cells were both clearly reduced in ATRA and ATPR groups.. ATPR could suppress the migration and invasion of A549 cells, and the mechanism might be concerned with down- regulating the expression of MLCK in the ERK-MAPK signaling pathway, pointing to therapeutic prospects in lung cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Movement; Cell Proliferation; Gene Expression Regulation, Enzymologic; Humans; Lung Neoplasms; Myosin-Light-Chain Kinase; Phosphorylation; Signal Transduction; Tretinoin; Tumor Cells, Cultured

The aim of the present study was to synthesize a series of retinamide derivatives using all-trans retinoic acid (ATRA) as raw material and observe their effects on the differentiation and apoptosis of human lung adenocarcinoma A549 cells. Four new synthesized ATRA retinamide derivatives were structurally confirmed by spectral analysis, including (1)H-NMR, (13)C-NMR, and MS. The results showed that the new ATRA retinamide derivatives significantly decreased the carcinoembryonic antigen secretion of A549 cells, significantly decreased the proliferation of A549 cells in a dose- and time-dependent manner, and promoted the apoptosis of A549 cells compared with ATRA. The Western blot assay indicated that the expression of Bcl-2 was decreased more in A549 cells treated with N-(3-trifluoromethylphenyl) retinamide than that in A549 cells treated with ATRA. The results also showed that the effects of N-(3-trifluoromethyl-phenyl) retinamide on differentiation and apoptosis were the strongest among the newly synthesized ATRA retinamide derivatives. Our results suggested that the effects of novel ATRA retinamide derivatives on increasing the differentiation, decreasing the proliferation, and promoting the apoptosis of A549 cells were greater than those of ATRA. The apoptosis of A549 cells induced by N-(3-trifluoromethylphenyl) retinamide may be related to downregulating the expression of Bcl-2.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Chromatin; DNA Fragmentation; DNA, Neoplasm; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Structure-Activity Relationship; Tretinoin

The synthetic retinoid, N-(4-hydroxyphenyl)retinamide (4HPR), which is currently being evaluated in clinical trials for cancer prevention and therapy, inhibits the growth of a variety of malignant cells through induction of apoptosis. However, in the majority of tumor cells, this inhibitory effect of 4HPR requires high concentrations (>1 microM), which exceed the peak plasma level measured in humans. In the present study, we compared and contrasted the effects of several synthetic retinamides on the growth of human lung and head and neck cancer cells in vitro. We found that some retinamides, especially N-(2-carboxyphenyl)retinamide (2CPR), exhibited better growth inhibitory effects than 4HPR in some of the cell lines. 2CPR exerted potent growth inhibitory effects in 5 of 10 head and neck cancer cell lines and in 1 of 10 lung cancer cell lines (IC(50), <0.8 microM). 2CPR (1 microM) induced apoptosis ranging from 10 to 60% in four of five cell lines, whereas 4HPR was ineffective at the same concentration. Unlike 4HPR, 2CPR (up to 10 microM) failed to induce reactive oxygen species production in these sensitive cell lines but could activate caspases 3 and 7 as well as increase poly(ADP-ribose)polymerase cleavage. Interestingly, the effect of 2CPR on cell growth could be suppressed by the specific retinoic acid receptor pan antagonist AGN193109. Our results suggest that 2CPR acts via retinoic acid receptors and may be a good candidate for prevention and treatment of some head and neck and lung cancers.

Topics: Anticarcinogenic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Fenretinide; Head and Neck Neoplasms; Humans; Lung Neoplasms; Reactive Oxygen Species; Receptors, Retinoic Acid; Retinoids; Tretinoin; Tumor Cells, Cultured