RRC ID 45374
Author Fuwa H, Sato M, Sasaki M.
Title Programmed cell death induced by (-)-8,9-dehydroneopeltolide in human promyelocytic leukemia HL-60 cells under energy stress conditions.
Journal Mar Drugs
Abstract (+)-Neopeltolide is a marine macrolide natural product that exhibits potent antiproliferative activity against several human cancer cell lines. Previous study has established that this natural product primarily targets the complex III of the mitochondrial electron transport chain. However, the biochemical mode-of-actions of neopeltolide have not been investigated in detail. Here we report that (-)-8,9-dehydroneopeltolide (8,9-DNP), a more accessible synthetic analogue, shows potent cytotoxicity against human promyelocytic leukemia HL-60 cells preferentially under energy stress conditions. Nuclear morphology analysis, as well as DNA ladder assay, indicated that 8,9-DNP induced significant nuclear condensation/fragmentation and DNA fragmentation, and these events could be suppressed by preincubating the cells with a pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD). Immunoblot analysis demonstrated the release of cytochrome c from the mitochondria and the cleavage of full-length caspase-3 and poly(ADP-ribose) polymerase (PARP). These results indicated that 8,9-DNP induced caspase-dependent apoptotic programmed cell death under energy stress conditions. It was also found that 8,9-DNP induced non-apoptotic cell death in the presence/absence of zVAD under energy stress conditions. Immunoblot analysis showed the intracytosolic release of apoptosis-inducing factor (AIF), although it did not further translocate to the nucleus. It appears most likely that, in the presence of zVAD, 8,9-DNP triggered necrotic cell death as a result of severe intracellular ATP depletion.
Volume 12(11)
Pages 5576-89
Published 2014-11-20
DOI 10.3390/md12115576
PII md12115576
PMID 25419998
PMC PMC4245546
MeSH Adenosine Triphosphate / metabolism Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Apoptosis Inducing Factor / metabolism Caspase 3 / metabolism Cell Death / drug effects Cytochromes c / metabolism DNA Fragmentation / drug effects HL-60 Cells Humans Leukemia, Promyelocytic, Acute / drug therapy* Leukemia, Promyelocytic, Acute / pathology Macrolides / pharmacology* Mitochondria / metabolism Oxazoles / pharmacology* Poly(ADP-ribose) Polymerases / metabolism
IF 4.073
Times Cited 7
Human and Animal Cells HL60