This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rousselot, P. Articles by Fermand, J.-P. Search for Related Content PubMed PubMed Citation Articles by Rousselot, P. Articles by Fermand, J.-P.

Arsenic Trioxide and Melarsoprol Induce Apoptosis in Plasma Cell Lines and in Plasma Cells from Myeloma Patients¹

Service d’Immuno-Hématologie and Laboratoire d’Immunopathologie [S. L., J-C. B., J-P. F.], Laboratoire de Biologie Cellulaire Hématopoïétique EP-107, Centre National de la Recherche Scientifique [P. R., J. L.], Laboratoire Central d’Hématologie [M-H. N.], and Laboratoire de Thérapie Cellulaire [J-P. M.], Hôpital Saint-Louis, 75475 Paris cedex 10, France

Recent data have renewed the interest for arsenic-containing compounds as anticancer agents. In particular, arsenic trioxide (As₂O₃) has been demonstrated to be an effective drug in the treatment of acute promyelocytic leukemia by inducing programmed cell death in leukemic cells both in vitro and in vivo. This prompted us to study the in vitro effects of As₂O₃ and of another arsenical derivative, the organic compound melarsoprol, on human myeloma cells and on the plasma cell differentiation of normal B cells.

At pharmacological concentrations (10^-8 to 10^-6 mol/L), As₂O₃ and melarsoprol caused a dose- and time-dependent inhibition of survival and growth in myeloma cell lines that was, in some, similar to that of acute promyelocytic leukemia cells. Both arsenical compounds induced plasma cell apoptosis, as assessed by 4',6-diamidino-2-phenylindole staining, detection of phosphatidylserine at the cell surface using annexin V, and by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. As₂O₃ and melarsoprol also inhibited viability and growth and induced apoptosis in plasma-cell enriched preparations from the bone marrow or blood of myeloma patients. In nonseparated bone marrow samples, both arsenical compounds triggered death in myeloma cells while sparing most myeloid cells, as demonstrated by double staining with annexin V and CD38 or CD15 antibodies. In primary myeloma cells as in cell lines, interleukin 6 did not prevent arsenic-induced cell death or growth inhibition, and no synergistic effect was observed with IFN-.

In contrast to As₂O₃, melarsoprol only slightly reduced the plasma cell differentiation of normal B cells induced by pokeweed mitogen. Both pokeweed mitogen-induced normal plasma cells and malignant plasma cells showed a normal nuclear distribution of PML protein, which was disrupted by As₂O₃ but not by melarsoprol, suggesting that the two arsenical derivatives acted by different mechanisms. These results point to the use of arsenical derivatives as investigational drugs in the treatment of multiple myeloma.

This article has been cited by other articles:

				S. M. Matulis, A. A. Morales, L. Yehiayan, C. Croutch, D. Gutman, Y. Cai, K. P. Lee, and L. H. Boise Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line Mol. Cancer Ther., May 1, 2009; 8(5): 1197 - 1206. [Abstract] [Full Text] [PDF]

				F. Binet and D. Girard Novel human neutrophil agonistic properties of arsenic trioxide: involvement of p38 mitogen-activated protein kinase and/or c-jun NH2-terminal MAPK but not extracellular signal-regulated kinases-1/2 J. Leukoc. Biol., December 1, 2008; 84(6): 1613 - 1622. [Abstract] [Full Text] [PDF]

				P. Lunghi, N. Giuliani, L. Mazzera, G. Lombardi, M. Ricca, A. Corradi, A. M. Cantoni, L. Salvatore, R. Riccioni, A. Costanzo, et al. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Blood, September 15, 2008; 112(6): 2450 - 2462. [Abstract] [Full Text] [PDF]

				A. A. Morales, D. Gutman, K. P. Lee, and L. H. Boise BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide-induced cell death in myeloma Blood, May 15, 2008; 111(10): 5152 - 5162. [Abstract] [Full Text] [PDF]

				T. A. Zykova, F. Zhu, C. Lu, L. Higgins, Y. Tatsumi, Y. Abe, A. M. Bode, and Z. Dong Lymphokine-Activated Killer T-Cell-Originated Protein Kinase Phosphorylation of Histone H2AX Prevents Arsenite-Induced Apoptosis in RPMI7951 Melanoma Cells Clin. Cancer Res., December 1, 2006; 12(23): 6884 - 6893. [Abstract] [Full Text] [PDF]

				G. Saunders Overview of drug therapy for multiple myeloma Journal of Oncology Pharmacy Practice, September 1, 2005; 11(3): 83 - 100. [Abstract] [PDF]

				G. McCollum, P. C. Keng, J. C. States, and M. J. McCabe Jr. Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G2/M Arrest in U937 Myeloid Leukemia Cells J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 877 - 887. [Abstract] [Full Text] [PDF]

				T. Kumagai, T. Ikezoe, D. Gui, J. O'Kelly, X.-J. Tong, F. J. Cohen, J. W. Said, and H. P. Koeffler RWJ-241947 (MCC-555), A Unique Peroxisome Proliferator-Activated Receptor-{gamma} Ligand with Antitumor Activity against Human Prostate Cancer in Vitro and in Beige/Nude/ X-Linked Immunodeficient Mice and Enhancement of Apoptosis in Myeloma Cells Induced by Arsenic Trioxide Clin. Cancer Res., February 15, 2004; 10(4): 1508 - 1520. [Abstract] [Full Text] [PDF]

				P. B. Tchounwou, A. K. Patlolla, and J. A. Centeno Invited Reviews: Carcinogenic and Systemic Health Effects Associated with Arsenic Exposure--A Critical Review Toxicol Pathol, October 1, 2003; 31(6): 575 - 588. [Abstract] [PDF]

				S. Gupta, L. Yel, D. Kim, C. Kim, S. Chiplunkar, and S. Gollapudi Arsenic Trioxide Induces Apoptosis in Peripheral Blood T Lymphocyte Subsets by Inducing Oxidative Stress: A Role of Bcl-2 Mol. Cancer Ther., August 1, 2003; 2(8): 711 - 719. [Abstract] [Full Text] [PDF]

				S. Sturlan, M. Baumgartner, E. Roth, and T. Bachleitner-Hofmann Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells Blood, June 15, 2003; 101(12): 4990 - 4997. [Abstract] [Full Text] [PDF]

				T. Kanzawa, Y. Kondo, H. Ito, S. Kondo, and I. Germano Induction of Autophagic Cell Death in Malignant Glioma Cells by Arsenic Trioxide Cancer Res., May 1, 2003; 63(9): 2103 - 2108. [Abstract] [Full Text] [PDF]

				N. J. Bahlis, J. McCafferty-Grad, I. Jordan-McMurry, J. Neil, I. Reis, M. Kharfan-Dabaja, J. Eckman, M. Goodman, H. F. Fernandez, L. H. Boise, et al. Feasibility and Correlates of Arsenic Trioxide Combined with Ascorbic Acid-mediated Depletion of Intracellular Glutathione for the Treatment of Relapsed/Refractory Multiple Myeloma Clin. Cancer Res., December 1, 2002; 8(12): 3658 - 3668. [Abstract] [Full Text] [PDF]

				A. Verma, M. Mohindru, D. K. Deb, A. Sassano, S. Kambhampati, F. Ravandi, S. Minucci, D. V. Kalvakolanu, and L. C. Platanias Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to Arsenic Trioxide J. Biol. Chem., November 15, 2002; 277(47): 44988 - 44995. [Abstract] [Full Text] [PDF]

				B. Lin, K. Podar, D. Gupta, Y.-T. Tai, S. Li, E. Weller, T. Hideshima, S. Lentzsch, F. Davies, C. Li, et al. The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584 Inhibits Growth and Migration of Multiple Myeloma Cells in the Bone Marrow Microenvironment Cancer Res., September 1, 2002; 62(17): 5019 - 5026. [Abstract] [Full Text] [PDF]

				T. Hayashi, T. Hideshima, M. Akiyama, P. Richardson, R. L. Schlossman, D. Chauhan, N. C. Munshi, S. Waxman, and K. C. Anderson Arsenic Trioxide Inhibits Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment Mol. Cancer Ther., August 1, 2002; 1(10): 851 - 860. [Abstract] [Full Text] [PDF]

				J. L. Slack, S. Waxman, G. Tricot, M. S. Tallman, and C. D. Bloomfield Advances in the Management of Acute Promyelocytic Leukemia and Other Hematologic Malignancies with Arsenic Trioxide Oncologist, April 1, 2002; 7(90001): 1 - 13. [Abstract] [Full Text] [PDF]

				M. A. Hussein Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma Oncologist, April 1, 2002; 7(90001): 20 - 29. [Abstract] [Full Text] [PDF]

				R. B. Gartenhaus, S. N. Prachand, M. Paniaqua, Y. Li, and L. I. Gordon Arsenic Trioxide Cytotoxicity in Steroid and Chemotherapy-resistant Myeloma Cell Lines: Enhancement of Apoptosis by Manipulation of Cellular Redox State Clin. Cancer Res., February 1, 2002; 8(2): 566 - 572. [Abstract] [Full Text] [PDF]

				K. Dvorakova, C. M. Payne, M. E. Tome, M. M. Briehl, M. A. Vasquez, C. N. Waltmire, A. Coon, and R. T. Dorr Molecular and Cellular Characterization of Imexon-resistant RPMI8226/I Myeloma Cells Mol. Cancer Ther., January 1, 2002; 1(3): 185 - 195. [Abstract] [Full Text] [PDF]

				B. J. Druker, S. G. O'Brien, J. Cortes, and J. Radich Chronic Myelogenous Leukemia Hematology, January 1, 2002; 2002(1): 111 - 135. [Abstract] [Full Text]

				S. Waxman and K. C. Anderson History of the Development of Arsenic Derivatives in Cancer Therapy Oncologist, April 1, 2001; 6(90002): 3 - 10. [Abstract] [Full Text]

				N. C. Munshi Arsenic Trioxide: An Emerging Therapy for Multiple Myeloma Oncologist, April 1, 2001; 6(90002): 17 - 21. [Abstract] [Full Text]

				A. J. Murgo Clinical Trials of Arsenic Trioxide in Hematologic and Solid Tumors: Overview of the National Cancer Institute Cooperative Research and Development Studies Oncologist, April 1, 2001; 6(90002): 22 - 28. [Abstract] [Full Text]

				M. J. McCabe Jr., K. P. Singh, S. A. Reddy, B. Chelladurai, J. G. Pounds, J. J. Reiners Jr., and J. C. States Sensitivity of Myelomonocytic Leukemia Cells to Arsenite-Induced Cell Cycle Disruption, Apoptosis, and Enhanced Differentiation Is Dependent on the Inter-Relationship between Arsenic Concentration, Duration of Treatment, and Cell Cycle Phase J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 724 - 733. [Abstract] [Full Text]

				K. Hossain, A. A. Akhand, M. Kato, J. Du, K. Takeda, J. Wu, K. Takeuchi, W. Liu, H. Suzuki, and I. Nakashima Arsenite Induces Apoptosis of Murine T Lymphocytes Through Membrane Raft-Linked Signaling for Activation of c-Jun Amino-Terminal Kinase J. Immunol., October 15, 2000; 165(8): 4290 - 4297. [Abstract] [Full Text] [PDF]

				G. J. Roboz, S. Dias, G. Lam, W. J. Lane, S. L. Soignet, R. P. Warrell Jr, and S. Rafii Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis Blood, August 15, 2000; 96(4): 1525 - 1530. [Abstract] [Full Text] [PDF]

				P. Costantini, E. Jacotot, D. Decaudin, and G. Kroemer Mitochondrion as a Novel Target of Anticancer Chemotherapy J Natl Cancer Inst, July 5, 2000; 92(13): 1042 - 1053. [Abstract] [Full Text] [PDF]

				W. H. Park, J. G. Seol, E. S. Kim, J. M. Hyun, C. W. Jung, C. C. Lee, B. K. Kim, and Y. Y. Lee Arsenic Trioxide-mediated Growth Inhibition in MC/CAR Myeloma Cells via Cell Cycle Arrest in Association with Induction of Cyclin-dependent Kinase Inhibitor, p21, and Apoptosis Cancer Res., June 1, 2000; 60(11): 3065 - 3071. [Abstract] [Full Text] [PDF]

				C. Perkins, C. N. Kim, G. Fang, and K. N. Bhalla Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-xL Blood, February 1, 2000; 95(3): 1014 - 1022. [Abstract] [Full Text] [PDF]

				Y. S. Lew, S. L. Brown, R. J. Griffin, C. W. Song, and J. H. Kim Arsenic Trioxide Causes Selective Necrosis in Solid Murine Tumors by Vascular Shutdown Cancer Res., December 1, 1999; 59(24): 6033 - 6037. [Abstract] [Full Text] [PDF]

				G. Kroemer and H. de The Arsenic Trioxide, a Novel Mitochondriotoxic Anticancer Agent? J Natl Cancer Inst, May 5, 1999; 91(9): 743 - 745. [Full Text] [PDF]

				E. M. Rego, L.-Z. He, R. P. Warrell Jr., Z.-G. Wang, and P. P. Pandolfi Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins PNAS, August 29, 2000; 97(18): 10173 - 10178. [Abstract] [Full Text] [PDF]