The Experts below are selected from a list of 939 Experts worldwide ranked by ideXlab platform
Peter J Sadler - One of the best experts on this subject based on the ideXlab platform.
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potent organo Osmium Compound shifts metabolism in epithelial ovarian cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Jessica M Hearn, Isolda Romerocanelon, Alison F Munro, Ana M Pizarro, Mathew J Garnett, Ultan Mcdermott, Neil O Carragher, Peter J SadlerAbstract:The organometallic “half-sandwich” Compound [Os(η 6 - p -cymene)(4-(2-pyridylazo)- N,N -dimethylaniline)I]PF 6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of Compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that Osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-Osmium Compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) Compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.
Stephen J Lippard - One of the best experts on this subject based on the ideXlab platform.
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bidentate ligands on Osmium vi nitrido complexes control intracellular targeting and cell death pathways
PMC, 2013Co-Authors: Kogularamanan Suntharalingam, Timothy C Johnstone, Peter M Bruno, Wei Lin, Michael T Hemann, Stephen J LippardAbstract:The cellular response evoked by antiproliferating Osmium(VI) nitrido Compounds of general formula OsN(N^N)Cl3 (N^N = 2,2′-bipyridine 1, 1,10-phenanthroline 2, 3,4,7,8-tetramethyl-1,10-phenanthroline 3, or 4,7-diphenyl-1,10-phenanthroline 4) can be tuned by subtle ligand modifications. Complex 2 induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, 4 evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, 4 is the first Osmium Compound to induce ER stress in cancer cells.
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Bidentate Ligands on Osmium(VI) Nitrido Complexes Control Intracellular Targeting and Cell Death Pathways
2013Co-Authors: Kogularamanan Suntharalingam, Timothy C Johnstone, Peter M Bruno, Wei Lin, Michael T Hemann, Stephen J LippardAbstract:The cellular response evoked by antiproliferating Osmium(VI) nitrido Compounds of general formula OsN(N^N)Cl3 (N^N = 2,2′-bipyridine 1, 1,10-phenanthroline 2, 3,4,7,8-tetramethyl-1,10-phenanthroline 3, or 4,7-diphenyl-1,10-phenanthroline 4) can be tuned by subtle ligand modifications. Complex 2 induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, 4 evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, 4 is the first Osmium Compound to induce ER stress in cancer cells
Jessica M Hearn - One of the best experts on this subject based on the ideXlab platform.
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potent organo Osmium Compound shifts metabolism in epithelial ovarian cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Jessica M Hearn, Isolda Romerocanelon, Alison F Munro, Ana M Pizarro, Mathew J Garnett, Ultan Mcdermott, Neil O Carragher, Peter J SadlerAbstract:The organometallic “half-sandwich” Compound [Os(η 6 - p -cymene)(4-(2-pyridylazo)- N,N -dimethylaniline)I]PF 6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of Compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that Osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-Osmium Compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) Compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.
Alison F Munro - One of the best experts on this subject based on the ideXlab platform.
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potent organo Osmium Compound shifts metabolism in epithelial ovarian cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Jessica M Hearn, Isolda Romerocanelon, Alison F Munro, Ana M Pizarro, Mathew J Garnett, Ultan Mcdermott, Neil O Carragher, Peter J SadlerAbstract:The organometallic “half-sandwich” Compound [Os(η 6 - p -cymene)(4-(2-pyridylazo)- N,N -dimethylaniline)I]PF 6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of Compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that Osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-Osmium Compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) Compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.
Ana M Pizarro - One of the best experts on this subject based on the ideXlab platform.
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potent organo Osmium Compound shifts metabolism in epithelial ovarian cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Jessica M Hearn, Isolda Romerocanelon, Alison F Munro, Ana M Pizarro, Mathew J Garnett, Ultan Mcdermott, Neil O Carragher, Peter J SadlerAbstract:The organometallic “half-sandwich” Compound [Os(η 6 - p -cymene)(4-(2-pyridylazo)- N,N -dimethylaniline)I]PF 6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of Compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that Osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-Osmium Compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) Compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.