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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.
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NEOPLASIA
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
From the Division of Hematology/Oncology, Department of Medicine, Department of Pathology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; and Pharmacyclics, Inc, Sunnyvale, CA.
Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because 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 50 µM MGd and 50 to 100 µM 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 patients with multiple myeloma. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders.
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