title: Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation.
abstract: While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1-1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-xL leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1.
authors.affiliation: 1] Chair of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany [2] Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Brockmann
authors.affiliation: Chair of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bluwstein
authors.affiliation: Chair of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kögel
authors.affiliation: Chair of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: May
authors.affiliation: 1] Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany [2] Chair of Organic Chemistry/Cellular Chemistry, Department of Chemistry, University of Konstanz, Konstanz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Marx
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: M P
authors.initials: MP
authors.lastname: Tschan
authors.affiliation: 1] Chair of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany [2] Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Brunner
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D018938:Caco-2 Cells; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013844:Thiazoles; D051020:bcl-X Protein; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin