Interleukin-6 affects melphalan-induced DNA damage and repair in human multiple myeloma cells.
In addition to signaling proliferation, growth factors may contribute to the persistence of hematopoietic tumors upon chemotherapeutical challenge. In multiple myeloma, malignant growth is mediated either by paracrine interleukin-6 (IL-6) elaborated by bone marrow stromal cells or via autocrine loops by malignant myeloma cells themselves. Although melphalan is one of the most active drugs in this tumor entity, the development of drug resistance frequently impedes cure of patients by attenuating melphalan-induced DNA-damage. We analyzed whether IL-6 protects XG-1 cells and plasma cells of a patient suffering from end-stage multiple myeloma (plasma cell leukemia) from melphalan with respect to DNA damage and DNA repair. Investigating the housekeeping gene glucose-6-phosphate dehydrogenase (G6PD) by using a PCR-stop assay, we found that there was more DNA damage in the G6PD gene of IL-6 deprived XG-1 and the patient's plasma cells, respectively, than in those with IL-6 supplementation. After cessation of melphalan exposure and 24 hours post-incubation in melphalan-free medium, DNA repair was observed in the patient's plasma cells but not in XG-1 cells. There was more DNA repair with IL-6 addition than without IL-6 addition. Similarly, the apoptotic cell fractions, as measured by flow cytometry, were lower if IL-6 was added to the medium. These results indicate that IL-6 may contribute to drug resistance in multiple myeloma.
Efferth
Thomas
T
Medizinische Klinik IV, RWTH Aachen, Germany. efferth@vcrp.de
Fabry
Ursula
U
Osieka
Rainhardt
R
D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005434:Flow Cytometry; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008558:Melphalan / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics*; D010950:Plasma Cells / Q000187:drug effects; D016133:Polymerase Chain Reaction
D018906:Antineoplastic Agents, Alkylating; D015850:Interleukin-6; D005954:Glucosephosphate Dehydrogenase; D008558:Melphalan