Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis

Rianne M. Lord, Andrew Hebden, Christopher M. Pask, Imogen R. Henderson, Simon J. Allison, Samantha L. Shepherd, Roger M. Phillips, Patrick C. McGowan

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

A series of ruthenium and iridium complexes have been synthesized and characterized with 20 novel crystal structures discussed. The library of β-ketoiminato complexes has been shown to be active against MCF-7 (human breast carcinoma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma), and A2780cis (cisplatin-resistant human ovarian carcinoma) cell lines, with selected complexes' being more than three times as active as cisplatin against the A2780cis cell line. Selected complexes were also tested against the noncancerous ARPE-19 (retinal pigment epithelial cells) cell line, in order to evaluate the complexes selectivity for cancer cells. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is overexpressed in cancer cells, and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anticancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant levels of cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double-strand DNA breaks or DNA cross-linking but induced significant levels of single-strand DNA breaks, indicating a mechanism of action different from that of cisplatin.

Original languageEnglish
Pages (from-to)4940-4953
Number of pages14
JournalJournal of Medicinal Chemistry
Volume58
Issue number12
Early online date3 Apr 2015
DOIs
Publication statusPublished - 25 Jun 2015

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Single-Stranded DNA Breaks
Coordination Complexes
Cell Death
Apoptosis
Cisplatin
Carcinoma
Cell Line
Neoplasms
Thioredoxin-Disulfide Reductase
Iridium
Retinal Pigments
Ruthenium
Double-Stranded DNA Breaks
DNA
Enzymes
Inhibitory Concentration 50
Libraries
Cause of Death
Cell Survival
Colon

Cite this

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title = "Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis",
abstract = "A series of ruthenium and iridium complexes have been synthesized and characterized with 20 novel crystal structures discussed. The library of β-ketoiminato complexes has been shown to be active against MCF-7 (human breast carcinoma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma), and A2780cis (cisplatin-resistant human ovarian carcinoma) cell lines, with selected complexes' being more than three times as active as cisplatin against the A2780cis cell line. Selected complexes were also tested against the noncancerous ARPE-19 (retinal pigment epithelial cells) cell line, in order to evaluate the complexes selectivity for cancer cells. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is overexpressed in cancer cells, and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anticancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant levels of cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double-strand DNA breaks or DNA cross-linking but induced significant levels of single-strand DNA breaks, indicating a mechanism of action different from that of cisplatin.",
author = "Lord, {Rianne M.} and Andrew Hebden and Pask, {Christopher M.} and Henderson, {Imogen R.} and Allison, {Simon J.} and Shepherd, {Samantha L.} and Phillips, {Roger M.} and McGowan, {Patrick C.}",
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Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis. / Lord, Rianne M.; Hebden, Andrew; Pask, Christopher M.; Henderson, Imogen R.; Allison, Simon J.; Shepherd, Samantha L.; Phillips, Roger M.; McGowan, Patrick C.

In: Journal of Medicinal Chemistry, Vol. 58, No. 12, 25.06.2015, p. 4940-4953.

Research output: Contribution to journalArticle

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T1 - Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis

AU - Lord, Rianne M.

AU - Hebden, Andrew

AU - Pask, Christopher M.

AU - Henderson, Imogen R.

AU - Allison, Simon J.

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AU - Phillips, Roger M.

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