Cell cycle regulation and induction of apoptosis by IL-6 variants on the multiple myeloma cell line XG-1

• Published in: Annals of hematology Vol. 78; no. 1; pp. 13 - 18
• Main Authors: PETRUCCI, M. T, RICCIARDI, M. R, ARIOLA, C, GREGORJ, C, RIBERSANI, M, SAVINO, R, CILIBERTO, G, TAFURI, A
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.01.1999; Springer Nature B.V
• Subjects: Antineoplastic agents; Apoptosis; Biological and medical sciences; Bone marrow; Bromodeoxyuridine; Cell culture; Cell Cycle; Cell survival; cyclin D1; DNA; DNA nucleotidylexotransferase; Flow Cytometry; Humans; Immunotherapy; Interleukin 6; Interleukin-6 - metabolism; Kinetics; Medical sciences; Multiple myeloma; Multiple Myeloma - metabolism; Multiple Myeloma - physiopathology; Pharmacology. Drug treatments; Plasma cells; regulatory proteins; Serum levels; Tumor cell lines; Tumor Cells, Cultured; Human; Immunopathology; Cytokine; Malignant hemopathy; Myeloma; In vitro; Interleukin 6; Variant; Treatment; Immunoglobulinopathy; Cell death; Lymphoproliferative syndrome; Immunotherapy; Cell cycle; Established cell line; Antagonist; Apoptosis; Biological receptor
• ISSN: 0939-5555; 1432-0584
• DOI: 10.1007/s002770050465

Interleukin-6 (IL-6) serum levels and the proliferative activity of bone marrow plasma cells have been described as important prognostic factors for survival duration in multiple myeloma (MM) patients. Since growth of neoplastic plasma cells is frequently promoted by IL-6, inhibition of its activity has been considered for the management of MM patients. With a similar rationale, IL-6 variants characterized by wild-type or increased affinity for the ligand-specific IL-6 alpha receptor chain and reduced ability to bind and/or dimerize the gp 130 chain have recently been generated. In the present study, the antiproliferative effects of the variants Sant1, Sant5, and Sant7, characterized by increasing antagonistic activity, were investigated by means of a detailed cell kinetic and apoptotic analysis of the IL-6-dependent MM XG-1 cell line. A significant reduction in the mean percent of XG-1 cells in active S-phase (DNA/bromodeoxyuridine incorporation) from 41% to 28.1% (p=0.04), 25.8% (p=0.04), and 15.3% (p=0.02), respectively, was observed using Sant1, Sant5, and Sant7. These effects were confirmed using the acridine-orange (AO) flow-cytometric technique, which showed a similar reduction of S-phase (34.2% of baseline value) in the presence of Sant1, Sant5, and Sant7, as well as a significant G1b arrest (from 44.5% to 47.6%, 48%, and 64.9%). Furthermore, IL-6 variants were capable of down-regulating the G1 cell cycle regulatory protein cyclin D1 expression. Cell cycle effects were coupled with a significant increase of apoptosis, measured by the AO and the terminal deoxynucleotidyl transferase assays, from 12.9% (control culture with IL-6) to 21.2% (Sant1), 29.1% (Sant5), and 23.5% (Sant7). These results were comparable to those obtained by depriving XG-1 of recombinant IL-6. Our study documents the antiproliferative activity exerted by IL-6 mutants on the XG-1 cell line, thus supporting the investigation of these molecules on primary MM cells.