Hearn, Jessica M., Romero-Canelón, Isolda, Qamar, Bushra, Liu, Zhe , Hands-Portman, Ian and Sadler, P. J. (2013) Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis. ACS Chemical Biology, Volume 8 (Number 6). pp. 1335-1343. doi:10.1021/cb400070a ISSN 1554-8929.

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Abstract

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology
Divisions:	Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre
Library of Congress Subject Headings (LCSH):	Antineoplastic agents, Antineoplastic agents -- Development, Iridium compounds, Organoiridium compounds, Organotransition metal compounds, Biochemistry, Mitochondria, Cell-mediated cytotoxicity
Journal or Publication Title:	ACS Chemical Biology
Publisher:	American Chemical Society
ISSN:	1554-8929
Official Date:	21 June 2013
Dates:	Date Event 21 June 2013 Published
Volume:	Volume 8
Number:	Number 6
Page Range:	pp. 1335-1343
DOI:	10.1021/cb400070a
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Date of first compliant deposit:	24 December 2015
Date of first compliant Open Access:	24 December 2015
Funder:	European Research Council (ERC), Birmingham Science City, Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Institute of Advanced Studies (IAS), University of Warwick Postgraduate Research Scholarship, University of Warwick
Grant number:	247450 (ERC)

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