Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid

• Published in: British journal of haematology 2007-08, Vol.138 (4), p.467-478
• Main Authors: Campbell, Richard A., Sanchez, Eric, Steinberg, Jeffrey A., Baritaki, Stavroula, Gordon, Melinda, Wang, Cathy, Shalitin, Dror, Chen, Haiming, Pang, Shen, Bonavida, Benjamin, Said, Jonathan, Berenson, James R.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antioxidants - therapeutic use; Apoptosis - drug effects; arsenic trioxide; Arsenicals - therapeutic use; Ascorbic Acid - therapeutic use; Biological and medical sciences; Boronic Acids - therapeutic use; Bortezomib; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulin G - analysis; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; melphalan; Melphalan - therapeutic use; Mice; Mice, SCID; multiple myeloma; Multiple Myeloma - drug therapy; Oxides - therapeutic use; Pyrazines - therapeutic use; severe combined immunodeficient mice; Xenograft Model Antitumor Assays
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2007.06675.x

Summary Arsenic trioxide (ATO) induces apoptosis of malignant plasma cells through multiple mechanisms, including inhibition of DNA binding by nuclear factor kappa‐B, a key player in the development of chemoresistance in multiple myeloma (MM). This activity suggests that ATO may be synergistic when combined with other active antimyeloma drugs. To evaluate this, we examined the antimyeloma effects of ATO alone and in combination with bortezomib, melphalan and ascorbic acid (AA) both in vitro and in vivo using a severe combined immunodeficient (SCID)‐hu murine myeloma model. Marked synergistic antimyeloma effects were demonstrated when human MM Los Angeles xenograft IgG lambda light chain (LAGλ‐1) cells were treated in vitro with ATO and any one of these agents. SCID mice bearing human MM LAGλ‐1 tumours were treated with single‐agent ATO, bortezomib, melphalan, or AA, or combinations of ATO with either bortezomib or melphalan and AA. Animals treated with any of these drugs alone showed tumour growth and increases in paraprotein levels similar to control mice, whereas animals treated with ATO‐containing combinations showed markedly suppressed tumour growth and significantly reduced serum paraprotein levels. These in vitro and in vivo results suggest that addition of ATO to other antimyeloma agents may result in improved outcomes for patients with relapsed or refractory MM.