Loading...
Hypoxia-Sensitive Metal β‑Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis
Lord, Rianne M. Hebden, A.J. Pask, C.M. Henderson, I.R. Allison, Simon J. Shepherd, S.L. Phillips, Roger M. McGowan, P.C.
Lord, Rianne M.
Hebden, A.J.
Pask, C.M.
Henderson, I.R.
Allison, Simon J.
Shepherd, S.L.
Phillips, Roger M.
McGowan, P.C.
Publication Date
2015-04-25
End of Embargo
Supervisor
Rights
Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
Institution
Department
Awarded
Embargo end date
Collections
Additional title
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.
Version
Accepted manuscript
Citation
Lord RM, Hebden AJ, Pask CM, Henderson IR, Allison SJ, Shepherd SL, Phillips RM, McGowan PC (2015) Hypoxia-Sensitive Metal β‑Ketoiminato Complexes Showing Induced
Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis. Journal of Medicinal Chemistry 58(12): 4940–4953.
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Article