4-Fluoro-N-butylphenylacetamide: a synthetic phenylacetate derivative that upregulates Bcl-X(S), activates caspase cascade and induces apoptosis in human squamous lung cancer CH27 cells.
Phenylacetate (PA) and related aromatic fatty acids induce antiproliferation and differentiation of cancer cell; they have potent anti-tumor properties with relatively low toxicity. To search for more potent analogues of PA, PA derivatives have been synthesized. In this study, we investigated the effects of six synthetic PA derivatives on the growth of human lung cancer cells. Results showed that the anti-proliferative effects of these synthetic compounds were strong than those of PA, 4-fluoro-N-butylphenylacetamide (H6) is the most potent compound. 4,6-Diamidino-2-phenylindole (DAPI) staining, in situ TUNEL assay and DNA gel electrophoresis analysis indicated that a marked reduction in the number of CH27 cells with H6 was related to the induction of apoptosis. The apoptosis triggered by H6 was accompanied by up-regulation of Bcl-X(S), accumulation of cytosolic cytochrome c and activation of caspase cascade (caspase-9 and -3). Furthermore, H6 induces proteolytic cleavage of poly (ADP-ribose) polymerase, which followed the appearance of caspase activity and preceded DNA fragmentation. Pretreatment with caspase inhibitors markedly inhibited H6-induced caspase activity and apoptosis. These results suggest that H6 may induce apoptosis through a Bcl-X(S) and caspase-dependent mechanism.
Chan
Hsu-Chin
HC
Department of Biochemistry, China Medical College, Taichung, Taiwan, ROC.
Kuo
Sheng-Chu
SC
Liu
Su-Chen
SC
Liu
Chung-Hsien
CH
Hsu
Shih-Lan
SL
D000081:Acetamides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002455:Cell Division; D002470:Cell Survival; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008956:Models, Chemical; D010648:Phenylacetates / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein
C470118:4-fluoro-N-butylphenylacetamide; D000081:Acetamides; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D010648:Phenylacetates; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; C025136:phenylacetic acid