Cytotoxicity and mitochondrial apoptosis induced by etoposide in melanoma cells.
Cytotoxicity and apoptosis induced by etoposide were studied during 72 hr in human melanoma cells. Etoposide initiated DNA-damage signaling via ATM kinase and activated p53 pathway and caspase-2. In response to treatment with etoposide, mitochondria of melanoma cells first increased their abundance and activity, and at later treatment intervals their dynamic behavior and functions became suppressed. Observed mitochondrial perturbation was not preceded by membrane potential loss but cytochrome c release was observed together with a rise in caspase-9 and caspase-3 activities. The pharmacological inhibition of relevant induced targets proved the importance of ATM and caspase-2 in etoposide-mediated cytotoxicity and apoptosis.
Rudolf
Kamil
K
Department of Rheumatology and Clinical Pharmacology, 2nd Internal Clinic, Faculty Teaching Hospital in Hradec Kralove, Sokolska Hradec Kralove, Czech Republic. rudolf@lfhk.cuni.cz
Cervinka
Miroslav
M
Rudolf
Emil
E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D052160:Benzothiazoles / Q000494:pharmacology; D053143:Caspase 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D052160:Benzothiazoles; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D014050:Toluene; D005047:Etoposide; D016572:Cyclosporine; D000255:Adenosine Triphosphate; C121565:pifithrin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C490360:CASP2 protein, human; D053143:Caspase 2; D053148:Caspase 3; D053453:Caspase 9; D003546:Cysteine Endopeptidases