Characterization of apoptosis induced by marine natural products in non small cell lung cancer A549 cells.
The effects of different marine derived agents were studied in A549 cell growth. These drugs induced cell cycle arrest at the G2-M phase associated with the up-regulation of GADD45alpha-gamma and down-regulation of c-Myc. In treated cells, GADD45alpha-gamma and c-Myc were up- and down-regulated, respectively. A cascade of events leading to apoptotic mitochondrial 'intrinsic' pathway was observed in treated cells: (1) dephosphorylation of BAD serine136; (2) BAD dissociation from 14-3-3 followed by its association with BCL-XL; (3) cytochrome c release; (4) caspase-3 activation, and (5) cleavage of vimentin. Caspase(s) inhibitor prevented the formation of cleavage products and, in turn, apoptosis was inhibited through a p53-independent mechanism. Moreover, these compounds did not activate NF-kappaB. Our findings may offer new insights into the mechanisms of action of these agents in A549 cells. The better understanding of their effects might be important to fully exploit the potential of these new drugs.
Catassi
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A
Translational Research B (Lung Cancer), Department of Integrated Medical Oncology (DOMI), National Cancer Research Institute, Largo Rosanna Benzi 10, 16132, Genoa, Italy.
Cesario
A
A
Arzani
D
D
Menichini
P
P
Alama
A
A
Bruzzo
C
C
Imperatori
A
A
Rotolo
N
N
Granone
P
P
Russo
P
P
D048948:14-3-3 Proteins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008387:Marine Toxins / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D000097642:GADD45 Proteins
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D045304:Cytochromes c; D008387:Marine Toxins; D016328:NF-kappa B; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014746:Vimentin; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C494819:BAD protein, human; C494811:BCL2L1 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C489427:MYC protein, human