Mitochondria and cellular energy metabolism in platinum chemotherapy

摘要: Chemotherapy is a major strategy in the treatment of cancer. Unfortunately, advanced cancers often fails due to tumor resistance chemotherapeutic drugs. Studies cell death signaling induced by agents are importance develop strategies for improved therapy, either development new drugs or potentiation existing Discovery markers prediction therapeutic outcome also great identification responsive patients and thereby treatment. This thesis presents results on apoptotic stress-signaling platinum drug cisplatin, combining with inhibitors metabolism as strategy. MEKK1, kinase MAPK-signaling pathway, was shown be responsible cisplatin activation mitochondrial proapoptotic protein Bak, seen conformational change this protein. However, Bak not sufficient induce apoptosis unless from another MAPK JNK, present. Gel filtration experiments revealed complexes sizes between 80 170 kDa cells cisplatininduced onset apoptosis. By chemical inhibition gene knock-out, JNK crucial formation these complexes. p53 involved responses Here, novel mechanism negative regulation translocation mitochondria presented. Induction iNOS after inhibit evaluated iNOS. There no upregulation oxaliplatin; however, addition exogenous nitric oxide abrogated drug. Seventeen clinical experimental were screened together glycolysis inhibitor 2-deoxyglucose (DG) fatty acid β-oxidation etomoxir HCT116 colon carcinoma cells. DG more potent than respect. Cytotoxic combination varied included apoptosis, necrosis growth arrest. The showed substantial increase response compared alone. Because ovarian cancer involves drugs, further studied two lines primary purified ascites. In lines, higher use glucose coupled increased carboplatin. cells, low expression β-F1-ATPase correlated reduced IC50 presence DG. LIST OF PUBLICATIONS I. Linda Strandberg Ihrlund, Emma Hernlund, Kristina Viktorsson, Theocharis Panaretakis, Gabor Barna, Kanaga Sabapathy, Stig Linder Maria C. Shoshan Two distinct pathways during stress signaling: Different roles MEKK1 JNK1 Exp Cell Res. 2006, 312: 1581-1589 II. Ozgur Kutuk, Huveyda Basaga, Linder, Panaretakis Cisplatin-induced nitrotyrosinylation prevents its Free Rad Biol Med. 2009 Jun 15;46(12):1607-13 III. Omar Khan, Yildiz O. Ates, Potentiation energy 2deoxyglucose Int J Cancer 2008 Jul 15;123(2):476-83 IV. Elisabet Hjerpe, Elisabeth Avall-Lundqvist Ovarian levels sensitive combined Mol Ther. Jul;8(7):1916-23 Additional publications: Ihrlund LS, Hernlund E, Khan O, MC 3-bromopyruvate tumour chemopotentiator Oncol Jun;2(1):94-101 Hellberg V, Wallin I, Eriksson S, Jerremalm Berndtsson M, Eksborg Arner ES, Ehrsson H, Laurell G Cisplatin oxaliplatin toxicity: cochlear kinetics determinant ototoxicity Natl Inst. Jan 7;101(1):37-47 MC, S Conditional screening shows that mitotic AKT/PKB-insensitive Chem Biol. Jun;2(2):81-7