Co-reporter:C. Lu;K. Laws;A. Eskandari;K. Suntharalingam
Dalton Transactions 2017 vol. 46(Issue 38) pp:12785-12789
Publication Date(Web):2017/10/03
DOI:10.1039/C7DT02789C
Tetranuclear copper(II) complexes containing multiple diclofenac and Schiff base moieties, 1–4, are shown to kill bulk cancer cells and cancer stem cells (CSCs) with low micromolar potency. The most effective complex, 1, elicits its cytotoxic effect by elevating the intracellular reactive oxygen species (ROS) levels and inhibiting cyclooxygenase-2 (COX-2) expression.
Co-reporter:Janine N. Boodram;Iain J. Mcgregor;Peter M. Bruno;Paul B. Cressey;Dr. Michael T. Hemann;Dr. Kogularamanan Suntharalingam
Angewandte Chemie International Edition 2016 Volume 55( Issue 8) pp:2845-2850
Publication Date(Web):
DOI:10.1002/anie.201510443
Abstract
The breast cancer stem cell (CSC) potency of a series of copper(II)–phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.
Co-reporter:Janine N. Boodram;Iain J. Mcgregor;Peter M. Bruno;Paul B. Cressey;Dr. Michael T. Hemann;Dr. Kogularamanan Suntharalingam
Angewandte Chemie 2016 Volume 128( Issue 8) pp:2895-2900
Publication Date(Web):
DOI:10.1002/ange.201510443
Abstract
The breast cancer stem cell (CSC) potency of a series of copper(II)–phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.
Co-reporter:Catherine R. Munteanu and Kogularamanan Suntharalingam
Dalton Transactions 2015 vol. 44(Issue 31) pp:13796-13808
Publication Date(Web):30 Jun 2015
DOI:10.1039/C5DT02101D
The evolution of resistance to traditional platinum-based anticancer drugs has compelled researchers to investigate the cytostatic properties of alternative transition metal-based compounds. The anticancer potential of cobalt complexes has been extensively studied over the last three decades, and much time has been devoted to understanding their mechanisms of action. This perspective catalogues the development of antiproliferative cobalt complexes, and provides an in depth analysis of their mode of action. Early studies on simple cobalt coordination complexes, Schiff base complexes, and cobalt–carbonyl clusters will be documented. The physiologically relevant redox properties of cobalt will be highlighted and the role this plays in the preparation of hypoxia selective prodrugs and imaging agents will be discussed. The use of cobalt-containing cobalamin as a cancer specific delivery agent for cytotoxins will also be described. The work summarised in this perspective shows that the biochemical and biophysical properties of cobalt-containing compounds can be fine-tuned to produce new generations of anticancer agents with clinically relevant efficacies.
Co-reporter:Arvin Eskandari, Janine N. Boodram, Paul B. Cressey, Chunxin Lu, Peter M. Bruno, Michael T. Hemann and Kogularamanan Suntharalingam
Dalton Transactions 2016 - vol. 45(Issue 44) pp:NaN17873-17873
Publication Date(Web):2016/10/13
DOI:10.1039/C6DT03811E
We report the cancer stem cell (CSC) potency of a novel series of copper(II)-phenanthroline complexes bearing nonsteriodial anti-inflammatory drugs: naproxen, tolfenamic acid, and indomethacin (2a–3c). Two of the complexes, 2a and 3c, kill breast CSC-enriched HMLER-shEcad cells (grown in both monolayer and three-dimensional cell cultures) to a significantly better extent than salinomycin, a well-established CSC toxin. The most potent complex in the series, 3c induces its cytotoxic effect by generating intracellular reactive oxygen species (ROS) and inhibiting cyclooxgenase-2 (COX-2) activity. Encapsulation of 3c using biodegradable methoxy poly(ethylene glycol)-b-poly(D,L-lactic-co-glycolic) acid (PEG–PLGA) copolymers at the appropriate feed (5%, 3c NP5) enhances breast CSC uptake and reduces overall toxicity. The nanoparticle formulation, 3c NP5 selectively kills breast CSCs over bulk breast cancer cells, and evokes a similar cellular response to the payload, 3c. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver CSC-potent metal complexes into CSCs.
Co-reporter:Catherine R. Munteanu and Kogularamanan Suntharalingam
Dalton Transactions 2015 - vol. 44(Issue 31) pp:NaN13808-13808
Publication Date(Web):2015/06/30
DOI:10.1039/C5DT02101D
The evolution of resistance to traditional platinum-based anticancer drugs has compelled researchers to investigate the cytostatic properties of alternative transition metal-based compounds. The anticancer potential of cobalt complexes has been extensively studied over the last three decades, and much time has been devoted to understanding their mechanisms of action. This perspective catalogues the development of antiproliferative cobalt complexes, and provides an in depth analysis of their mode of action. Early studies on simple cobalt coordination complexes, Schiff base complexes, and cobalt–carbonyl clusters will be documented. The physiologically relevant redox properties of cobalt will be highlighted and the role this plays in the preparation of hypoxia selective prodrugs and imaging agents will be discussed. The use of cobalt-containing cobalamin as a cancer specific delivery agent for cytotoxins will also be described. The work summarised in this perspective shows that the biochemical and biophysical properties of cobalt-containing compounds can be fine-tuned to produce new generations of anticancer agents with clinically relevant efficacies.
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