[en] We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(p-cymene)(1,10-phenanthroline)Cl]PF6 motif (where M is either RuII or OsII) with an appended C16 fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C16 OsII nanomedicines as highly successful in vivo. Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we examined the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism.
Disciplines :
Pharmacy, pharmacology & toxicology Chemistry
Author, co-author :
Marloye, Mickaël; Microbiology, Bioorganic & Macromolecular Chemistry, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
Inam, Haider; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA
Moore, Connor J; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA
Mertens, Tyler R; Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
Ingels, Aude; Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
Koch, Marilin; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Nowicki, Michal O; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Mathieu, Véronique; Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium ; ULB Cancer Research Center (UCRC), Université libre de Bruxelles (ULB), 1050 Brussels, Belgium
Pritchard, Justin R; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA
Awuah, Samuel G ; Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
Lawler, Sean E; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Meyer, Franck ; Microbiology, Bioorganic & Macromolecular Chemistry, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
Berger, Gilles ; Université de Mons - UMONS ; Microbiology, Bioorganic & Macromolecular Chemistry, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium ; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
R550 - Institut des Sciences et Technologies de la Santé
Funders :
Fédération Wallonie-Bruxelles Belgian Brain Tumor Support Fonds De La Recherche Scientifique - FNRS
Funding text :
M. M. thanks Véronique Megalizzi and Michel Gelbcke for helpful discussions and guidance on the analysis of video microscopy experiments, the team of the Analytical Platform of the Faculty of Pharmacy (ULB) for the record of MS spectra and the team of G-time laboratory (ULB) for the ICP-MS experiments. We would also like to thank Dr Tomoko Sengoku and Mr Michael Alstott for the support with our redox metabolism experiments, supported by the shared resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). This research was partially funded by NCI R50 CA243706-02 for MON, NCI R01 CA258421-01 for SGA, by the Fédération Wallonie-Bruxelles (EG/MA/JCD/CBV 19-24) for M. M. and by the Belgian Brain Tumor Support (BBTS) for V. M.; G. B. was the recipient of an FRS-FNRS award.
Rosenberg B. Van Camp L. Krigas T. Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode Nature 1965 205 698 699
Go R. S. Adjei A. A. Review of the Comparative Pharmacology and Clinical Activity of Cisplatin and Carboplatin J. Clin. Oncol. 2012 17 409 422
Desoize B. Madoulet C. Particular aspects of platinum compounds used at present in cancer treatment Crit. Rev. Oncol. Hematol. 2002 42 317 325
Kelland L. The resurgence of platinum-based cancer chemotherapy Nat. Rev. Cancer 2007 7 573 584
Einhorn L. H. Treatment of testicular cancer: a new and improved model J. Clin. Oncol. 1990 8 1777 1781
Florea A.-M. Büsselberg D. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects Cancers 2011 3 1351 1371
Hector S. Bolanowska-Higdon W. Zdanowicz J. Hitt S. Pendyala L. In vitro studies on the mechanisms of oxaliplatin resistance Cancer Chemother. Pharmacol. 2001 48 398 406
Stewart D. J. Mechanisms of resistance to cisplatin and carboplatin Crit. Rev. Oncol. Hematol. 2007 63 12 31
Galluzzi L. Senovilla L. Vitale I. Michels J. Martins I. Kepp O. Castedo M. Kroemer G. Molecular mechanisms of cisplatin resistance Oncogene 2012 31 1869 1883
Medici S. Peana M. Nurchi V. M. Lachowicz J. I. Crisponi G. Zoroddu M. A. Noble metals in medicine: latest advances Coord. Chem. Rev. 2014 1 22
Mari C. Gasser G. Lightening up Ruthenium Complexes to Fight Cancer? Chimia 2015 69 176 181
Bergamo A. Gaiddon C. Schellens J. H. M. Beijnen J. H. Sava G. Approaching tumour therapy beyond platinum drugs: Status of the art and perspectives of ruthenium drug candidates J. Inorg. Biochem. 2012 106 90 99
Meier-Menches S. M. Gerner C. Berger W. Hartinger C. G. Keppler B. K. Structure-activity relationships for ruthenium and osmium anticancer agents - towards clinical development Chem. Soc. Rev. 2018 47 909 928
Hanif M. Babak M. V. Hartinger C. G. Development of anticancer agents: wizardry with osmium Drug Discovery Today 2014 19 1640 1648
Liu Z. Sadler P. J. Organoiridium complexes: anticancer agents and catalysts Acc. Chem. Res. 2014 47 1174 1185
Leung C. H. Zhong H. J. Chan D. S. H. Ma D. L. Bioactive iridium and rhodium complexes as therapeutic agents Coord. Chem. Rev. 2013 257 1764 1776
Cini M. Bradshaw T. D. Woodward S. Using titanium complexes to defeat cancer: The view from the shoulders of titans Chem. Soc. Rev. 2017 46 1040 1051
Caruso F. Rossi M. Pettinari C. Anticancer titanium agents Expert Opin. Ther. Pat. 2001 11 969 979
Leonidova A. Gasser G. Underestimated Potential of Organometallic Rhenium Complexes as Anticancer Agents ACS Chem. Biol. 2014 9 10 2180 2193
Bauer E. B. Haase A. A. Reich R. M. Crans D. C. Kühn F. E. Organometallic and coordination rhenium compounds and their potential in cancer therapy Coord. Chem. Rev. 2019 393 79 117
Mertens R. T. Jennings W. C. Ofori S. Kim J. H. Parkin S. Kwakye G. F. Awuah S. G. Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function JACS Au 2021 1 439 449
Mertens R. T. Parkin S. Awuah S. G. Cancer cell-selective modulation of mitochondrial respiration and metabolism by potent organogold(III) dithiocarbamates Chem. Sci. 2020 11 10465 10482
Gukathasan S. Parkin S. Awuah S. G. Cyclometalated Gold(III) Complexes Bearing DACH Ligands Inorg. Chem. 2019 58 9326 9340
Kim J. H. Reeder E. Parkin S. Awuah S. G. Gold(I/III)-Phosphine Complexes as Potent Antiproliferative Agents Sci. Rep. 2019 9 1 18
Berger W. Keppler B. K. NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application Chem. Sci. 2014 5 2925 2932
Leijen S. Burgers S. A. Baas P. Pluim D. Tibben M. Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy Invest. New Drugs 2015 33 201 214
Trondl R. Heffeter P. Kowol C. R. Jakupec M. A. Berger W. Keppler B. K. NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application Chem. Sci. 2014 5 2925 2932
Aird R. E. Cummings J. Ritchie A. A. Muir M. Morris R. E. Chen H. Sadler P. J. Jodrell D. I. In vitro and in vivo activity and cross resistance profiles of novel ruthenium(II) organometallic arene complexes in human ovarian cancer Br. J. Cancer 2002 86 1652 1657
Scolaro C. Bergamo A. Brescacin L. Delfino R. Cocchietto M. Laurenczy G. Geldbach T. J. Sava G. Dyson P. J. In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes J. Med. Chem. 2005 48 4161 4171
Meier-menches S. M. Gerner C. Hartinger C. G. Keppler B. K. Structure-activity relationships for ruthenium and osmium anticancer agents - towards clinical development Chem. Soc. Rev. 2018 47 909 928
Zhang P. Sadler P. J. Advances in the design of organometallic anticancer complexes J. Organomet. Chem. 2017 839 5 14
Peacock A. F. A. Habtemariam A. Fernández R. Walland V. Fabbiani F. P. A. Parsons S. Aird R. E. Jodrell D. I. Sadler P. J. Tuning the reactivity of osmium(II) and ruthenium(II) arene complexes under physiological conditions J. Am. Chem. Soc. 2006 128 1739 1748
Cebria B. Krokhin A. A. Stepanenko I. N. Eichinger R. Jakupec M. A. Arion V. B. Keppler B. K. Osmium NAMI-A Analogues: Synthesis, Structural and Spectroscopic Characterization, and Antiproliferative Properties Inorg. Chem. 2007 46 1739 1748
Shnyder S. D. Fu Y. Habtemariam A. Van Rijt S. H. Cooper P. A. Loadman P. M. Sadler P. J. Anti-colorectal cancer activity of an organometallic osmium arene azopyridine complex MedChemComm 2011 2 666 668
Needham R. J. Sanchez-Cano C. Zhang X. Romero-Canelón I. Habtemariam A. Cooper M. S. Meszaros L. Clarkson G. J. Blower P. J. Sadler P. J. In-Cell Activation of Organo-Osmium(II) Anticancer Complexes Angew. Chem., Int. Ed. 2017 56 1017 1020
Hearn J. M. Romero-Canelón I. Munro A. F. Fu Y. Pizarro A. M. Garnett M. J. McDermott U. Carragher N. O. Sadler P. J. Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells Proc. Natl. Acad. Sci. U. S. A. 2015 112 E3800 E3805
Zheng Y.-R. Suntharalingam K. Johnstone T. C. Yoo H. Lin W. Brooks J. G. Lippard S. J. Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery J. Am. Chem. Soc. 2014 136 8790 8798
Palmucci J. Marchetti F. Pettinari R. Pettinari C. Scopelliti R. Riedel T. Therrien B. Galindo A. Dyson P. J. Synthesis, structure, and anticancer activity of arene-ruthenium(II) complexes with acylpyrazolones bearing aliphatic groups in the acyl moiety Inorg. Chem. 2016 55 11770 11781
Svensson F. R. Matson M. Li M. Lincoln P. Biophysical Chemistry Lipophilic ruthenium complexes with tuned cell membrane af fi nity and photoactivated uptake Biophys. Chem. 2010 149 102 106
Khan F. Therrien B. Süss-fink G. Zava O. Dyson P. J. Arene ruthenium dichloro complexes containing isonicotinic ester ligands: Synthesis, molecular structure and cytotoxicity J. Organomet. Chem. 2013 730 49 56
Colina-vegas L. Villarreal W. Navarro M. Rodrigues C. Oliveira D. Graminha A. E. Ivo P. Maia S. De V. M. Ferreira A. G. Regina M. Batista A. A. Cytotoxicity of Ru(II) piano - stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA J. Inorg. Biochem. 2015 153 150 161
Betanzos-Lara S. Novakova O. Deeth R. J. Pizarro A. M. Clarkson G. J. Liskova B. Brabec V. Sadler P. J. Habtemariam A. Bipyrimidine ruthenium(II) arene complexes: structure, reactivity and cytotoxicity J. Biol. Inorg. Chem. 2012 17 1033 1051
Peacock A. F. A. Habtemariam A. Moggach S. A. Prescimone A. Parsons S. Sadler P. J. Uni V. Road W. M. Eh E. Chloro Half-Sandwich Osmium(II) Complexes: Influence of Chelated N,N-Ligands on Hydrolysis, Guanine Binding, and Cytotoxicity Inorg. Chem. 2007 46 2966 2967
Ashton T. M. Gillies McKenna W. Kunz-Schughart L. A. Higgins G. S. Oxidative phosphorylation as an emerging target in cancer therapy Clin. Cancer Res. 2018 24 2482 2490
Sun W. Li S. Häupler B. Liu J. Jin S. Steffen W. Schubert U. S. Butt H. J. Liang X. J. Wu S. An Amphiphilic Ruthenium Polymetallodrug for Combined Photodynamic Therapy and Photochemotherapy In Vivo Adv. Mater. 2017 29 6 1603702
Kołoczek P. Skórska-Stania A. Cierniak A. Sebastian V. Komarnicka U. K. Płotek M. Kyzioł A. Polymeric micelle-mediated delivery of half-sandwich ruthenium(II) complexes with phosphanes derived from fluoroloquinolones for lung adenocarcinoma treatment Eur. J. Pharm. Biopharm. 2018 128 69 81
Estalayo-Adrián S. Blasco S. Bright S. A. McManus G. J. Orellana G. Williams D. C. Kelly J. M. Gunnlaugsson T. Water-soluble amphiphilic ruthenium(II) polypyridyl complexes as potential light-activated therapeutic agents Chem. Commun. 2020 56 9332 9335
Clavel C. M. Pǎunescu E. Nowak-Sliwinska P. Dyson P. J. Thermoresponsive organometallic arene ruthenium complexes for tumour targeting Chem. Sci. 2014 5 1097 1101
Reitman Z. Winkler F. Elia A. New directions in the treatment of glioblastoma Semin. Neurol. 2018 38 50 61
Lathia J. Mack S. Cancer stem cells in glioblastoma Genes 2015 29 1203 1217
Fang J. Nakamura H. Maeda H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect Adv. Drug Delivery Rev. 2011 63 136 151
Schweizer F. Cationic amphiphilic peptides with cancer-selective toxicity Eur. J. Pharmacol. 2009 625 190 194
Burdick M. D. Harris A. Reid C. J. Iwamura T. Hollingsworth M. A. Oligosaccharides expressed on MUC1 produced by pancreatic and colon tumor cell lines J. Biol. Chem. 1997 272 24198 24202
Fidler I. J. Schroit A. J. Connor J. Bucana C. D. Fidler I. J. Elevated Expression of Phosphatidylserine in the Outer Membrane Leaflet of Human Tumor Cells and Recognition by Activated Human Blood Monocytes Cancer Res. 1991 51 3062 3066
Kleeff J. Ishiwata T. Kumbasar A. Friess H. Büchler M. W. Lander A. D. Korc M. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer J. Clin. Invest. 1998 102 1662 1673
Lee H. S. Park C. B. Kim J. M. Jang S. A. Park I. Y. Kim M. S. Cho J. H. Kim S. C. Mechanism of anticancer activity of buforin IIb, a histone H2A-derived peptide Cancer Lett. 2008 271 47 55
Curry S. Brick P. Franks N. P. Fatty acid binding to human serum albumin: new insights from crystallographic studies Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 1999 1441 131 140
Sathyadevi P. Krishnamoorthy P. Bhuvanesh N. S. P. Kalaiselvi P. Vijaya V. Dharmaraj N. Organometallic ruthenium(II) complexes: Synthesis, structure and in fluence of substitution at azomethine carbon towards DNA/BSA binding, radical scavenging and cytotoxicity Eur. J. Med. Chem. 2012 55 420 431
Ghuman J. Zunszain P. A. Petitpas I. Bhattacharya A. A. Otagiri M. Curry S. Structural basis of the drug-binding specificity of human serum albumin J. Mol. Biol. 2005 353 38 52
Beckford F. A. Reaction of the Anticancer Organometallic Ruthenium Compound, [(η6-p-Cymene)Ru(ATSC)Cl]PF6 with Human Serum Albumin Int. J. Inorg. Chem. 2010 975756
Lehrer S. S. Solute Perturbation of Protein Fluorescence. The Quenching of the Tryptophyl Fluorescence of Model Compounds and of Lysozyme by Iodide Ion Biochemistry 1971 10 3254 3263
Cacita N. Nikolaou S. Studying the interaction between trinuclear ruthenium complexes and human serum albumin by means of fluorescence quenching J. Lumin. 2016 169 115 120
Wang F. Habtemariam A. van der Geer E. P. L. Fernández R. Melchart M. Deeth R. J. Aird R. Guichard S. Fabbiani F. P. A. Lozano-Casal P. Oswald I. D. H. Jodrell D. I. Parsons S. Sadler P. J. Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity Proc. Natl. Acad. Sci. U. S. A. 2005 102 18269 18274
Betanzos-lara S. Novakova O. Deeth R. J. Pizarro A. M. Clarkson G. J. Liskova B. Brabec V. Sadler P. J. Habtemariam A. Bipyrimidine ruthenium(II) arene complexes: structure, reactivity and cytotoxicity J. Biol. Inorg. Chem. 2012 17 1033 1051
Raber J. Zhu C. Eriksson L. A. Activation of anti-cancer drug cisplatin—is the activated complex fully aquated? Mol. Phys. 2004 102 2537 2541
Perumareddi J. R. Adamson A. W. Photochemistry of Complex Ions. V. The Photochemistry of Some Square-Planar Platinum(II) Complexes J. Org. Phys. Chem. 1967 3774 414 420
Balendiran G. K. Dabur R. Fraser D. The role of glutathione in cancer Cell Biochem. Funct. 2004 22 343 352
Dougan S. J. Melchart M. Habtemariam A. Parsons S. Sadler P. J. Phenylazo-pyridine and phenylazo-pyrazole chlorido ruthenium(II) arene complexes: Arene loss, aquation, and cancer cell cytotoxicity Inorg. Chem. 2006 45 10882 10894
Tobita H. Hasegawa K. Josephus J. Minglana G. Luh L. Okazaki M. Ogino H. Extremely Facile Arene Exchange on a Ruthenium(II) Complex Having a Novel Bis (silyl) Chelate Ligand (Xantsil) Organometallics 1999 2058 2060
Delaude L. Delfosse S. Richel A. Demonceau A. Noels A. F. Tuning of ruthenium N-heterocyclic carbene catalysts for ATRP Chem. Commun. 2003 1526 1527
Schmid W. F. John R. O. Arion V. B. Jakupec M. A. Keppler B. K. Highly Antiproliferative Ruthenium(II) and Osmium(II) Arene Complexes with Paullone-Derived Ligands Organometallics 2007 6643 6652
Miyajima A. Nakashima J. Tachibana M. Nakamura K. Hayakawa M. Murai M. N-acetylcysteine modifies cis-dichlorodiammineplatinum-induced effects in bladder cancer cells Jpn. J. Cancer Res. 1999 90 565 570
Sullivan M. P. Nieuwoudt M. K. Bowmaker G. A. Lam N. Y. S. Truong D. Goldstone D. C. Hartinger C. G. Unexpected arene ligand exchange results in the oxidation of an organoruthenium anticancer agent: the first X-ray structure of a protein-Ru(carbene) adduct Chem. Commun. 2018 54 6120 6123
Fu Y. Habtemariam A. Pizarro A. M. Van Rijt S. H. Healey D. J. Cooper P. A. Shnyder S. D. Clarkson G. J. Sadler P. J. Organometallic osmium arene complexes with potent cancer cell cytotoxicity J. Med. Chem. 2010 53 8192 8196
Sorenson C. M. Barry M. A. Eastman A. Analysis of Events Associated With Cell Cycle Arrest at G2 Phase and Cell Death Induced by Cisplatin J. Natl. Cancer Inst. 1990 82 9 749 755
Romero-Canelón I. Salassa L. Sadler P. J. The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo- and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway J. Med. Chem. 2013 56 1291 1300
Mühlgassner G. Bartel C. Schmid W. F. Jakupec M. A. Arion V. B. Keppler B. K. Biological activity of ruthenium and osmium arene complexes with modified paullones in human cancer cells J. Inorg. Biochem. 2012 116 180 187
Tan C. P. Lu Y. Y. Ji L. N. Mao Z. W. Metallomics insights into the programmed cell death induced by metal-based anticancer compounds Metallomics 2014 6 978 995
Speranza M. C. Passaro C. Ricklefs F. Kasai K. Klein S. R. Nakashima H. Kaufmann J. K. Ahmed A. K. Nowicki M. O. Obi P. Bronisz A. Aguilar-Cordova E. Aguilar L. K. Guzik B. W. Breakefield X. Weissleder R. Freeman G. J. Reardon D. A. Wen P. Y. Chiocca E. A. Lawler S. E. Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma Neuro-Oncology 2018 20 225 235
Choi Y. M. Kim H. K. Shim W. Anwar M. A. Kwon J. W. Kwon H. K. Kim H. J. Jeong H. Kim H. M. Hwang D. Kim H. S. Choi S. Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation PLoS One 2015 10 1 21
Luo Y. Fu Y. Huang Z. Li M. Transition metals and metal complexes in autophagy and diseases J. Cell. Physiol. 2021 236 7144 7158
Fulda S. Kögel D. Cell death by autophagy: Emerging molecular mechanisms and implications for cancer therapy Oncogene 2015 34 5105 5113
Kondo Y. Kondo S. Autophagy and Cancer Therapy Autophagy 2006 85 90
Tan C. Lai S. Wu S. Hu S. Zhou L. Chen Y. Wang M. Zhu Y. Nuclear Permeable Ruthenium(II) β-Carboline Complexes Induce Autophagy To Antagonize Mitochondrial-Mediated Apoptosis J. Med. Chem. 2010 7613 7624
Ettore Porporato P. Filigheddu N. Bravo-San Pedro J. M. Kroemer G. Galluzzi L. Mitochondrial metabolism and cancer Cell Res. 2018 28 265 280
Jiang H. Pritchard J. R. Williams R. T. Lauffenburger D. A. Hemann M. T. A mammalian functional-genetic approach to characterizing cancer therapeutics Nat. Chem. Biol. 2010 7 1 9
Pritchard J. R. Bruno P. M. Hemann M. T. Lauffenburger D. A. Predicting cancer drug mechanisms of action using molecular network signatures Mol. Biosyst. 2013 9 1604 1619
Pritchard J. R. Bruno P. M. Gilbert L. A. Capron K. L. Lauffenburger D. A. Hemann M. T. Defining principles of combination drug mechanisms of action Proc. Natl. Acad. Sci. U. S. A. 2012 110 170 179
Vakifahmetoglu-norberg H. Xia H. Vakifahmetoglu-norberg H. Xia H. Yuan J. Pharmacologic agents targeting autophagy Find the latest version: Pharmacologic agents targeting autophagy J. Clin. Invest. 2015 125 5 13
Kovacs A. L. Reith A. Seglen P. O. Accumulation of autphagosomes after inhibition of hepatocytic protein degradation by vinblastine, leupeptin or a lysosomotropic amine Exp. Cell Res. 1982 137 191 201
Fu Y. Soni R. Romero M. J. Pizarro A. M. Salassa L. Clarkson G. J. Hearn J. M. Habtemariam A. Wills M. Sadler P. J. Mirror-image organometallic osmium arene iminopyridine halido complexes exhibit similar potent anticancer activity Chemistry 2013 19 15199 15209
Alatrash N. Issa F. H. Bawazir N. S. West S. J. Van Manen-Brush K. E. Shelor C. P. Dayoub A. S. Myers K. A. Janetopoulos C. Lewis E. A. MacDonnell F. M. Disruption of microtubule function in cultured human cells by a cytotoxic ruthenium(II) polypyridyl complex Chem. Sci. 2020 11 264 275
Meier S. M. Kreutz D. Winter L. Klose M. H. M. Cseh K. Weiss T. Bileck A. Alte B. Mader J. C. Jana S. Chatterjee A. Bhattacharyya A. Hejl M. Jakupec M. A. Heffeter P. Berger W. Hartinger C. G. Keppler B. K. Wiche G. Gerner C. An Organoruthenium Anticancer Agent Shows Unexpected Target Selectivity For Plectin Angew. Chem., Int. Ed. 2017 56 1 6
Singh S. K. Hawkins C. Clarke I. D. Squire J. A. Bayani J. Hide T. Henkelman R. M. Cusimano M. D. Dirks P. B. Identification of human brain tumour initiating cells Nature 2004 432 396 401
Galli R. Binda E. Orfanelli U. Cipelletti B. Gritti A. De Vitis S. Fiocco R. Foroni C. Dimeco F. Vescovi A. Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma Cancer Res. 2004 64 7011 7021
Suntharalingam K. Lin W. Johnstone T. C. Bruno P. M. Zheng Y.-R. Hemann M. T. Lippard S. J. A Breast Cancer Stem Cell Selective, Mammospheres Potent Osmium(VI) Nitrido Complex J. Am. Chem. Soc. 2014 136 14413 14416
Berger G. Grauwet K. Zhang H. Hussey A. M. Nowicki M. O. Wang D. I. Chiocca E. A. Lawler S. E. Lippard S. J. Anticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models Cancer Lett. 2018 416 138 148
Janiszewska M. Suvà M. L. Riggi N. Houtkooper R. H. Auwerx J. Clément-Schatlo V. Radovanovic I. Rheinbay E. Provero P. Stamenkovic I. Imp2 controls oxidative phosphorylation and is crucial for preservin glioblastoma cancer stem cells Genes Dev. 2012 26 1926 1944
Vlashi E. Lagadec C. Vergnes L. Matsutani T. Masui K. Poulou M. Popescu R. Della Donna L. Evers P. Dekmezian C. Reue K. Christofk H. Mischel P. S. Pajonka F. Metabolic state of glioma stem cells and nontumorigenic cells Proc. Natl. Acad. Sci. U. S. A. 2011 108 16062 16067
Ishiguro T. Ohata H. Sato A. Yamawaki K. Enomoto T. Okamoto K. Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications Cancer Sci. 2017 108 283 289
Rotem A. Janzer A. Izar B. Ji Z. Doench J. G. Garraway L. A. Struhl K. Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation Proc. Natl. Acad. Sci. U. S. A. 2015 112 5708 5713
Shi Y. Lim S. K. Liang Q. Iyer S. V. Wang H. Y. Wang Z. Xie X. Sun D. Chen Y. J. Tabar V. Gutin P. Williams N. De Brabander J. K. Parada L. F. Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma Nature 2019 567 341 346
Sighel D. Notarangelo M. Aibara S. Re A. Ricci G. Guida M. Soldano A. Adami V. Ambrosini C. Broso F. Rosatti E. F. Longhi S. Buccarelli M. D'Alessandris Q. G. Giannetti S. Pacioni S. Ricci-Vitiani L. Rorbach J. Pallini R. Roulland S. Amunts A. Mancini I. Modelska A. Quattrone A. Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth Cell Rep. 2021 35 109024
Laws K. Bineva-Todd G. Eskandari A. Lu C. O'Reilly N. Suntharalingam K. A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells Angew. Chem., Int. Ed. 2018 57 287 291
Awuah S. G. Kim J. H. Ofori S. Mertens R. T. Parkin S. Water-soluble gold(III)-Metformin complex alters mitochondrial bioenergetics in breast cancer cells ChemMedChem 2021 16 15 3222 3230
