title: Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells.
abstract: Alkylating agents are widely used chemotherapeutics in the treatment of many cancers, including leukemia, lymphoma, multiple myeloma, sarcoma, lung, breast and ovarian cancer. Melphalan is the most commonly used chemotherapeutic agent against multiple myeloma. However, despite a 70-80% initial response rate, virtually all patients eventually relapse due to the emergence of drug-resistant tumour cells. By using global proteomic and transcriptomic profiling on melphalan sensitive and resistant RPMI8226 cell lines followed by functional assays, we discovered changes in cellular processes and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further explored to elucidate their potential to overcome melphalan resistance.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Kamila Anna
authors.initials: KA
authors.lastname: Zub
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Mirta Mittelstedt Leal de
authors.initials: MM
authors.lastname: Sousa
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sarno
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway; PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Animesh
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Aida
authors.initials: A
authors.lastname: Demirovic
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Shalini
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Clifford
authors.initials: C
authors.lastname: Young
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Per Arne
authors.initials: PA
authors.lastname: Aas
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Ericsson
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Ole Nørregaard
authors.initials: ON
authors.lastname: Jensen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway; PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Slupphaug
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008558:Melphalan / Q000494:pharmacology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D020543:Proteome / Q000187:drug effects / Q000235:genetics; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016209:Interleukin-8; D020543:Proteome; D042461:Vascular Endothelial Growth Factor A; D008558:Melphalan