title: Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL-induced cancer cell apoptosis via stimulation of mitochondrial pathway.
abstract: In search for novel strategies in colon cancer treatment, we investigated the unique ability of platinum(IV) complex LA-12 to efficiently enhance the killing effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and compared it with the sensitizing action of cisplatin. We provide the first evidence that LA-12 primes human colon cancer cells for TRAIL-induced cytotoxicity by p53-independent activation of the mitochondrial apoptotic pathway. The cooperative action of LA-12 and TRAIL was associated with stimulation of Bax/Bak activation, drop of mitochondrial membrane potential, caspase-9 activation, and a shift of the balance among Bcl-2 family proteins in favor of the pro-apoptotic members. In contrast to cisplatin, LA-12 was a potent inducer of ERK-mediated Noxa and BimL protein upregulation, and more effectively enhanced TRAIL-induced apoptosis in the absence of Bax. The cooperative action of LA-12 and TRAIL was augmented following the siRNA-mediated silencing of Mcl-1 in both Bax proficient/deficient cells. We newly demonstrated that LA-12 induced ERK-mediated c-Myc upregulation, and proved that c-Myc silencing inhibited the mitochondrial activation and apoptosis in colon cancer cells treated with LA-12 and TRAIL. The LA-12-mediated sensitization to TRAIL-induced apoptosis was demonstrated in several colon cancer cell lines, further underscoring the general relevance of our findings. The selective action of LA-12 was documented by preferential priming of cancer but not normal colon cancer cells to TRAIL killing effects. Our work highlights the promising potential of LA-12 over cisplatin to enhance the colon cancer cell sensitivity to TRAIL-induced apoptosis, and provides new mechanistic insights into their cooperative action.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic; Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic. Electronic address: ivina@ibp.cz.
authors.forename: Iva
authors.initials: I
authors.lastname: Jelínková
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic; Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic. Electronic address: safarikova@ibp.cz.
authors.forename: Barbora
authors.initials: B
authors.lastname: Šafaříková
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic. Electronic address: olgablanarova@seznam.cz.
authors.forename: Olga
authors.initials: O
authors.lastname: Vondálová Blanářová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic; Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic. Electronic address: belma@ibp.cz.
authors.forename: Belma
authors.initials: B
authors.lastname: Skender
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic; Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic. Electronic address: hofmanova@ibp.cz.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Hofmanová
authors.affiliation: Platinum Pharmaceuticals, a.s., Brno, Czech Republic. Electronic address: peter.owl@seznam.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Sova
authors.affiliation: INCELL Corporation LLC, San Antonio, TX, USA. Electronic address: mpmoyer@incell.com.
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic; Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic. Electronic address: kozubik@ibp.cz.
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.affiliation: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic. Electronic address: kolarz@tunw.upol.cz.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Kolář
authors.affiliation: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic. Electronic address: erman@tunw.upol.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Ehrmann
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic; Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Ann's University Hospital Brno, Brno, Czech Republic. Electronic address: vaculova@ibp.cz.
authors.forename: Alena
authors.initials: A
authors.lastname: Hyršlová Vaculová
mesh_terms: D000547:Amantadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016158:Genes, p53; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); D000547:Amantadine; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; Colon cancer; LA-12; TRAIL