Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper-thiosemicarbazone complexes

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Abstract

The combination of cytotoxic copper ''thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity'' allowing minimization of the more toxic copper ''thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper ''thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts.
Original languageEnglish
Pages (from-to)407-419
Number of pages13
JournalJournal of Biological Inorganic Chemistry
Volume21
Issue number3
DOIs
Publication statusPublished - Jun 2016

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MCF-7 Cells
Cytotoxicity
Thiosemicarbazones
Oxidation-Reduction
Copper
Reactive Oxygen Species
Cells
Cell Line
Fibroblasts
Oxygen
Poisons
Cell death
Therapeutics
Pharmaceutical Preparations
Adenocarcinoma
Breast
Cell Death
Safety
copper-thiosemicarbazone complex

Cite this

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title = "Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper-thiosemicarbazone complexes",
abstract = "The combination of cytotoxic copper ''thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity'' allowing minimization of the more toxic copper ''thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper ''thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts.",
keywords = "Benzophenoxazine, Copper, Cytotoxicity, Reactive oxygen species (ROS), Thiosemicarbazone",
author = "Fady Akladios and Scott Andrew and Christopher Parkinson",
note = "Imported on 12 Apr 2017 - DigiTool details were: month (773h) = June; Journal title (773t) = Journal of Biological Inorganic Chemistry. ISSNs: 0949-8257;",
year = "2016",
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doi = "10.1007/s00775-016-1350-2",
language = "English",
volume = "21",
pages = "407--419",
journal = "Journal of Biological Inorganic Chemistry",
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TY - JOUR

T1 - Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper-thiosemicarbazone complexes

AU - Akladios, Fady

AU - Andrew, Scott

AU - Parkinson, Christopher

N1 - Imported on 12 Apr 2017 - DigiTool details were: month (773h) = June; Journal title (773t) = Journal of Biological Inorganic Chemistry. ISSNs: 0949-8257;

PY - 2016/6

Y1 - 2016/6

N2 - The combination of cytotoxic copper ''thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity'' allowing minimization of the more toxic copper ''thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper ''thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts.

AB - The combination of cytotoxic copper ''thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity'' allowing minimization of the more toxic copper ''thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper ''thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts.

KW - Benzophenoxazine

KW - Copper

KW - Cytotoxicity

KW - Reactive oxygen species (ROS)

KW - Thiosemicarbazone

U2 - 10.1007/s00775-016-1350-2

DO - 10.1007/s00775-016-1350-2

M3 - Article

C2 - 26951232

VL - 21

SP - 407

EP - 419

JO - Journal of Biological Inorganic Chemistry

JF - Journal of Biological Inorganic Chemistry

SN - 0949-8257

IS - 3

ER -