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Preclinical evaluation of 4‐[3,5‐bis(2‐chlorobenzylidene)‐4‐oxo‐piperidine‐1‐yl]‐4‐oxo‐2‐butenoic acid, in a mouse model of lung cancer xenograft
Author(s) -
Yadav Vivek R,
Sahoo Kaustuv,
Awasthi Vibhudutta
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12406
Subject(s) - apoptosis , cancer research , cyclin d1 , survivin , in vivo , microbiology and biotechnology , lung cancer , chemistry , biology , pathology , medicine , cell cycle , biochemistry
Background and Purpose 4‐[3,5‐Bis(2‐chlorobenzylidene)‐4‐oxo‐piperidine‐1‐yl]‐4‐oxo‐2‐butenoic acid CLEFMA is a new anti‐cancer molecule. Here, we investigated changes in apoptosis and inflammatory markers during CLEFMA ‐induced tumour suppression. Experimental Approach Lung adenocarcinoma H441 and A549 , and normal lung fibroblast CCL151 cell lines were used, along with a xenograft model of H441 cells implanted in mice. Tumour tissues were analysed by immunoblotting, immunohistochemistry and/or biochemical assays. The ex vivo results were confirmed by performing selected assays in cultured cells. Key Results CLEFMA ‐induced cell death was associated with cleavage of caspases 3/9 and PARP . In vivo, CLEFMA treatment resulted in a dose‐dependent suppression of tumour growth and 18 F ‐fluorodeoxyglucose uptake in tumours, along with a reduction in the expression of the proliferation marker Ki ‐67. In tumour tissue homogenates, the anti‐apoptotic markers (cellular inhibitor of apoptosis protein‐1( cIAP1 ), Bcl ‐xL, Bcl ‐2, and survivin) were inhibited and the pro‐apoptotic Bax and BID were up‐regulated. Further, CLEFMA decreased translocation of phospho‐p65– NF ‐κ B into the nucleus. In vitro , it inhibited the DNA ‐binding and transcriptional activity of NF ‐κ B . It also reduced the expression of COX ‐2 in tumours and significantly depressed serum TNF ‐α and IL ‐6 levels. These effects of CLEFMA were accompanied by a reduced transcription and/or translation of the invasion markers VEGF , MMP9 , MMP10 , Cyclin D1 and ICAM‐1 . Conclusions and Implications Overall, CLEFMA inhibited growth of lung cancer xenografts and this tumour suppression was associated with NF ‐κ B ‐regulated anti‐inflammatory and anti‐metastatic effects.