TY - JOUR
T1 - Pyrophosphate-bridged complexes with picomolar toxicity
AU - Ikotun, Oluwatayo F.
AU - Higbee, Elizabeth M.
AU - Ouellette, Wayne
AU - Doyle, Robert P.
N1 - Funding Information:
We thank the Alliance of Graduate Education and the Professoriate Program (AGEP) for a fellowship to O.F.I, the iLEARN program (for support for E.M.B), and Syracuse University for funding. We are grateful to Nerissa Viola-Villegas for confocal microscopy training, Gillian V. Kupakuwana for fluorimeter training and Dr. Deborah Kerwood for assistance with the 31 P NMR (All at SU Department of Chemistry).
PY - 2009/9
Y1 - 2009/9
N2 - Recently, we have observed the emergence of a new series of pyrophosphate-bridged coordination complexes. Such complexes have been prepared by overcoming the ready hydrolysis of the pyrophosphate moiety. To date, no exploration has been conducted on the cytotoxicity of such complexes. Three pyrophosphate-bridged complexes, namely {[Ni(phen)2]2(μ-P2O7)}·27H2O, {[Cu(phen)(H2O)]2(μ-P2O7)}·8H2O and {[Co(phen)2]2(μ-P2O7)}·6MeOH, (where phen is 1,10′-phenanthroline) were chosen for their comparative structural similarities and suitable aqueous solubility. Cytotoxicity studies in the adriamycin-resistant ovarian cancer cell line A2780/AD demonstrated highly significant efficacy, with values as low as 160 pM for the cobalt complex at 72 h. The underlying mechanism for such exceptional toxicity is investigated focusing on DNA interactions, topoisomerase I enzyme inhibition and oxidative stress (followed by intracellular glutathione levels). The role of hydrolysis in uptake and toxicity is also explored (followed by electronic absorption spectroscopy, 31P NMR, and confocal microscopy) and the complexes are compared to cisplatin controls. Overall a clear picture of the extraordinary toxicity emerged. The results demonstrate a new class of prodrugs with significant potential for future development for the treatment of drug-resistant cancer cell lines.
AB - Recently, we have observed the emergence of a new series of pyrophosphate-bridged coordination complexes. Such complexes have been prepared by overcoming the ready hydrolysis of the pyrophosphate moiety. To date, no exploration has been conducted on the cytotoxicity of such complexes. Three pyrophosphate-bridged complexes, namely {[Ni(phen)2]2(μ-P2O7)}·27H2O, {[Cu(phen)(H2O)]2(μ-P2O7)}·8H2O and {[Co(phen)2]2(μ-P2O7)}·6MeOH, (where phen is 1,10′-phenanthroline) were chosen for their comparative structural similarities and suitable aqueous solubility. Cytotoxicity studies in the adriamycin-resistant ovarian cancer cell line A2780/AD demonstrated highly significant efficacy, with values as low as 160 pM for the cobalt complex at 72 h. The underlying mechanism for such exceptional toxicity is investigated focusing on DNA interactions, topoisomerase I enzyme inhibition and oxidative stress (followed by intracellular glutathione levels). The role of hydrolysis in uptake and toxicity is also explored (followed by electronic absorption spectroscopy, 31P NMR, and confocal microscopy) and the complexes are compared to cisplatin controls. Overall a clear picture of the extraordinary toxicity emerged. The results demonstrate a new class of prodrugs with significant potential for future development for the treatment of drug-resistant cancer cell lines.
KW - Co complexes
KW - Confocal microscopy
KW - Cu complexes
KW - Cytotoxicity
KW - DNA interactions
KW - Ni complexes
KW - Oxidative stress
KW - Pyrophosphate
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U2 - 10.1016/j.jinorgbio.2009.07.010
DO - 10.1016/j.jinorgbio.2009.07.010
M3 - Article
C2 - 19666193
AN - SCOPUS:68949212839
SN - 0162-0134
VL - 103
SP - 1254
EP - 1264
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
IS - 9
ER -