Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide

• Published in: Blood Vol. 88; no. 5; pp. 1805 - 1812
• Main Authors: TU, Y, XU, F.-H, LIU, J, VESCIO, R, BERENSON, J, FADY, C, LICHTENSTEIN, A
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 01.09.1996
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Base Sequence; Biological and medical sciences; Culture Media, Serum-Free - pharmacology; Dexamethasone - pharmacology; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - genetics; Etoposide - pharmacology; fas Receptor - physiology; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Humans; Hydrogen Peroxide - pharmacology; Medical sciences; Molecular Sequence Data; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Pharmacology. Drug treatments; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Human; Immunopathology; DNA topoisomerase (ATP-hydrolysing); Enzyme; Podophyllotoxin derivative; Hydrogenperoxides; Enzyme inhibitor; Cytotoxicity; Malignant hemopathy; Gene expression; Myeloma; In vitro; Antibiotic; Isomerases; Immunoglobulinopathy; Lymphoproliferative syndrome; C-Onc gene; Established cell line; Anthracyclins; Antimitotic; Negative therapeutic reaction; Protooncogene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v88.5.1805.1805

Enhanced expression of the antiapoptotic gene BCL-2 may participate in chemoresistance. To ascertain if multiple myeloma cells surviving exposure to chemotherapy alter their BCL-2 expression, we treated the myeloma cell lines 8226, IM-9, and U266 as well as a primary myeloma cell culture with various injurious agents. Doxorubicin, etoposide, and hydrogen peroxide consistently induced a concentration- and time-dependent upregulation of BCL-2 expression in all myeloma target cell types assayed by flow cytometry and Western blot analysis. In contrast, serum starvation, dexamethasone, and anti-fas antibodies had no effect on expression. Enhanced expression of BCL-2 was relatively selective as treatments had no effect on expression of Ig light chains, BCL-X, or actin. An reverse transcriptase-polymerase chain reaction assay showed increased levels of BCL-2 RNA in 8226 cells as early as 4 hours after treatment with doxorubicin at a time when cell recoveries were not decreased. Thus, doxorubicin stimulates BCL-2 expression in individual 8226 cells rather than simply allowing a selected survival of high BCL-2-expressing cells in culture. Doxorubicin-treated 8226 cells with upregulated BCL-2 expression were relatively resistant to a second exposure of doxorubicin. In addition, BCL-2-transfected IM-9 cells, with enhanced expression of BCL-2 which was comparable to that achieved by initial exposure to doxorubicin, were resistant to doxorubicin and etoposide cytotoxicity. These data suggest that exposure to chemotherapeutic agents may enhance BCL-2 expression in surviving myeloma cells and contribute to acquired chemoresistance.