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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1265-1273. Prepublished online as a Blood First Edition Paper on September 23, 2004; DOI 10.1182/blood-2004-03-0964. This Article Full Text (PDF) All Versions of this Article: 2004-03-0964v1 105/3/1265    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Evens, A. M Articles by Gordon, L. I Search for Related Content PubMed PubMed Citation Articles by Evens, A. M Articles by Gordon, L. I Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 12, 2004 Accepted September 16, 2004 Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells Andrew M Evens, Philip Lecane, Darren Magda, Sheila Prachand, Seema Singhal, Jeff Nelson, Richard A Miller, Ronald B Gartenhaus, and Leo I Gordon* Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA Pharmacyclics, Inc, Sunnyvale, CA, USA Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA; University of Maryland Greenbaum Cancer Center, Baltimore, MD, USA * Corresponding author; email: l-gordon{at}northwestern.edu. Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Since redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414), chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells. We found complete inhibition of proliferation and cytotoxicity in each sensitive and resistant cell line with 24-hour exposure to clinically relevant concentrations of 50µM MGd and 50µM-100µM of ascorbate, which was required for the effect. The mechanism of cytotoxicity was related to induction of apoptosis as demonstrated by alteration in mitochondrial membrane potential and elevated annexin-V expression. This was accompanied by depletion of intracellular glutathione and increased ROS production. Moreover, catalase substantially abrogated MGd-induced cell death. Using fluorescence microscopy and flow cytometry, we found intracellular uptake of MGd and intracellular ROS production. MGd also induced apoptosis in fresh malignant cells from multiple myeloma patients. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Evens, W. G. Spies, I. B. Helenowski, D. Patton, S. Spies, B. D. Jovanovic, S. Miyata, E. Hamilton, D. Variakojis, J. Chen, et al. The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with [90Y]Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin's Lymphoma: Preclinical Findings and Results of a Phase I Trial Clin. Cancer Res., October 15, 2009; 15(20): 6462 - 6471. [Abstract] [Full Text] [PDF] S. Bhalla, S. Balasubramanian, K. David, M. Sirisawad, J. Buggy, L. Mauro, S. Prachand, R. Miller, L. I. Gordon, and A. M. Evens PCI-24781 Induces Caspase and Reactive Oxygen Species-Dependent Apoptosis Through NF-{kappa}B Mechanisms and Is Synergistic with Bortezomib in Lymphoma Cells Clin. Cancer Res., May 15, 2009; 15(10): 3354 - 3365. [Abstract] [Full Text] [PDF] T. Dragovich, M. Gordon, D. Mendelson, L. Wong, M. Modiano, H.-H. S. Chow, B. 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[Abstract] [Full Text] [PDF] L. Yu, F. Wan, S. Dutta, S. Welsh, Z. Liu, E. Freundt, E. H. Baehrecke, and M. Lenardo Autophagic programmed cell death by selective catalase degradation PNAS, March 28, 2006; 103(13): 4952 - 4957. [Abstract] [Full Text] [PDF] P. S. Lecane, M. W. Karaman, M. Sirisawad, L. Naumovski, R. A. Miller, J. G. Hacia, and D. Magda Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines Cancer Res., December 15, 2005; 65(24): 11676 - 11688. [Abstract] [Full Text] [PDF]

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