Caspase-independence and characterization of bisnaphthalimidopropyl spermidine induced cytotoxicity in HL60 cells

Caspase-independence and characterization of bisnaphthalimidopropyl spermidine induced cytotoxicity in HL60 cells

Bisnaphthalimides are DNA intercalators of potential use as chemotherapeutics but for which the range of mechanism of action is only gradually being elucidated. Using human promyelocytic HL-60 cells, we extend characterization of the cytotoxicity of bisnaphthalimidopropylspermidine (BNIPSpd) and exa...

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Bibliographic Details
Published in:Toxicology in vitro Vol. 52; pp. 342 - 350
Main Authors: Bestwick, Charles S., Milne, Lesley, Dance, Anne-Marie, Cochennec, Gaela, Cruickshank, Gillian, Allain, Eflamm, Constable, Lynda, Duthie, Susan J., Thoo Lin, Paul Kong
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01-10-2018
Elsevier Science Ltd
Subjects:
Apoptosis
Bisnaphthalimides
Breakage
Caspase inhibitors
Caspase-inhibition
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA damage
DNA fragmentation
Exposure
Flow cytometry
Genotoxicity
HL-60 cells
Ladders
Membranes
Phosphatidylserine
Polyamines
Spermidine
Toxicity
Viability
Caspase-inhibition
OPA
Genotoxicity
Cytotoxicity
PI
Bisnaphthalimides
HL-60 cells
BNIPSpd
Apoptosis
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Summary:Bisnaphthalimides are DNA intercalators of potential use as chemotherapeutics but for which the range of mechanism of action is only gradually being elucidated. Using human promyelocytic HL-60 cells, we extend characterization of the cytotoxicity of bisnaphthalimidopropylspermidine (BNIPSpd) and examine the relationship with caspase-activity. Within 4 h exposure, BNIPSpd (1–10 μM) induced significant DNA strand breakage. Evidence of apoptosis was progressive through the experimental period. Within 6 h, BNIPSpd increased the proportion of cells exhibiting plasma membrane phosphatidylserine exposure. Within 12 h, active caspase expression increased and was sustained with 5 and 10 μM BNIPSpd. Flow cytometric analysis revealed caspase activity in cells with and without damaged membranes. By 24 h, 5 and 10 μM BNIPSpd increased hypodiploid DNA content and internucleosomal DNA fragmentation (DNA ladders) typical of the later stages of apoptosis. 1 μM BNIPSpd exposure also increased hypodiploid DNA content by 48 h. Polyamine levels decreased by 24 h BNIPSpd exposure. The pan-caspase inhibitor, z-VAD-fmk, significantly decreased DNA degradation (hypodiploid DNA and DNA ladders) and cytotoxicity. Despite this, cell growth and viability remained significantly impaired. We propose that BNIPSpd cytotoxicity arises through DNA damage and not polyamine depletion and that cytotoxicity is dominated by but not dependent upon caspase driven apoptosis.
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ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2018.06.023