This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 McCafferty-Grad, J. Articles by Boise, L. H. Search for Related Content PubMed PubMed Citation Articles by McCafferty-Grad, J. Articles by Boise, L. H.

¹ Sylvester Cancer Center, ² Department of Microbiology and Immunology, and ³ Division of Hematology and Oncology, University of Miami School of Medicine, Miami, FL; and ⁴ Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

Requests for Reprints: Lawrence Boise, Department of Microbiology and Immunology, University of Miami School of Medicine, P. O. Box 016960 (R-138), Miami, FL 33101. Phone: (305) 243-6137; Fax: (305) 243-6903. E-mail: lboise{at}med.miami.edu

Arsenic trioxide (ATO) is emerging as a standard therapy for refractory acute promyelocytic leukemia. Consequently, ATO-based therapies are being investigated in other cancers. We have reported that the combination of ATO and ascorbic acid is an effective strategy in chemoresistant myeloma cell lines and in plasma cells from patients. ATO action is multimodal and appears to involve thiol depletion, increased reactive oxygen species production, loss of mitochondrial membrane potential (_m), and activation of caspases. To better define the ATO death pathway, we asked whether caspase activity is required for ATO-mediated cell death. Here we report that ATO exerts cytotoxic effects in myeloma cell lines via both caspase-dependent and caspase-independent pathways. We monitored ATO-induced changes in cell viability, caspase activity, superoxide production, and _m in the presence or absence of the caspase inhibitors t-butoxy carbonyl-Asp.fluoromethylketone (BocD.fmk) and Z-Val-Ala-Asp.fluoromethylketone (zVAD.fmk) and the anti-oxidant N-acetylcysteine. Consistent with glutathione levels dictating ATO action, N-acetylcysteine abrogated ATO-induced changes in cell death, caspase activation, free radical production, and loss of _m in all the cell lines we tested. Experiments with caspase inhibitors suggested at least two models for ATO death signaling. In 8226/S cells, blockade of caspases had no effect on loss of cell viability, increase in reactive oxygen species production, and minimal effects on the loss of _m. In contrast, BocD.fmk or zVAD.fmk conferred significant protection from the effects of ATO in U266 cells and MM1.S cells. Chemoresistant variants of 8226/S and MM1.S displayed similar ATO-induced death pathways as their respective parental lines. Studies with myeloma cells from bone marrow biopsies indicated that ATO initiates a caspase-independent pathway in the majority of samples.

Key Words: Arsenic trioxide • Caspases • Myeloma • Cell death • Chemoresistance

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Grant support: Supported in part by R29CA77837 (L.H.B.), a senior research grant from the Multiple Myeloma Research Foundation (L.H.B.), RO1CA97243 (K.P.L., L.H.B.), an American Institute for Cancer Research postdoctoral award (J.M-G.), and an American Society of Clinical Oncology Young Investigator Award (N.J.B.).

Note: Current address for N.J.B.: Division of Hematology and Oncology, BRB 3rd Floor # West, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4937.

Received 11/19/02; revised 8/ 6/03; accepted 8/15/03.

This article has been cited by other articles:

				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]

				K. Ishitsuka, T. Hideshima, M. Hamasaki, N. Raje, S. Kumar, H. Hideshima, N. Shiraishi, H. Yasui, A. M. Roccaro, P. Richardson, et al. Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis Blood, September 1, 2005; 106(5): 1794 - 1800. [Abstract] [Full Text] [PDF]

				A. Chin, S. Liu, J. Ting-Chan, and M. A. Gill Extended stability of ascorbic acid in 5% dextrose injection and 0.9% sodium chloride injection Am. J. Health Syst. Pharm., May 15, 2005; 62(10): 1073 - 1074. [Full Text] [PDF]

				L. E. Broker, F. A.E. Kruyt, and G. Giaccone Cell Death Independent of Caspases: A Review Clin. Cancer Res., May 1, 2005; 11(9): 3155 - 3162. [Abstract] [Full Text] [PDF]

				O. Sordet, Z. Liao, H. Liu, S. Antony, E. V. Stevens, G. Kohlhagen, H. Fu, and Y. Pommier Topoisomerase I-DNA Complexes Contribute to Arsenic Trioxide-induced Apoptosis J. Biol. Chem., August 6, 2004; 279(32): 33968 - 33975. [Abstract] [Full Text] [PDF]