Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow microenvironment.
Multiple myeloma (MM) remains incurable with current therapies, and novel biologically based therapies are urgently needed. Thalidomide and its analogues, as well as proteasome inhibitors, are examples of such novel agents that target both the myeloma cell and its microenvironment and can overcome classical drug resistance. In this study we demonstrate that arsenic trioxide (As2O3) mediates anti-MM activity both directly on tumor cells and indirectly by inhibiting production of myeloma growth and survival factors in the bone marrow (BM) microenvironment. Specifically, As2O3 at clinically achievable levels (2-5 microM) induces apoptosis even of drug-resistant MM cell lines and patient cells via caspase-9 activation, enhances the MM cell apoptosis induced by dexamethasone, and can overcome the antiapoptotic effects of interleukin 6. As2O3 also acts in the BM microenvironment to decrease MM cell binding to BM stromal cells, inhibits interleukin 6 and vascular endothelial growth factor secretion induced by MM cell adhesion, and blocks proliferation of MM cells adherent to BM stromal cells. These studies provide the rationale for clinical trials of As2O3, either alone or together with dexamethasone, to overcome classical drug resistance and improve outcome in patients with MM.
Hayashi
Toshiaki
T
The Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hideshima
Teru
T
Akiyama
Masaharu
M
Richardson
Paul
P
Schlossman
Robert L
RL
Chauhan
Dharminder
D
Munshi
Nikhil C
NC
Waxman
Samuel
S
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D016228:Endothelial Growth Factors / Q000378:metabolism; D004789:Enzyme Activation; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy*; D010087:Oxides / Q000494:pharmacology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D001152:Arsenicals; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008222:Lymphokines; D010087:Oxides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D000077237:Arsenic Trioxide