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J. Biol. Chem., Vol. 278, Issue 41, 39461-39469, October 10, 2003
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Suppression of NF-
B Survival Signaling by Nitrosylcobalamin Sensitizes Neoplasms to the Anti-tumor Effects of Apo2L/TRAIL*
¶ ¶ ||
From the
Taussig Cancer Center, Center for Cancer Drug Discovery and Development and the ¶Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195
We have previously demonstrated the anti-tumor activity of nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. The specific aim of this study was to examine whether NO-Cbl could sensitize drug-resistant melanomas to Apo2L/TRAIL. Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL and confirmed by examining levels and activity of key mediators of apoptosis. The activation status of NF-
B was established by assaying DNA binding, luciferase reporter activity, the phosphorylation status of IB
, and in vitro IKK activity. NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. Treatment with NO-Cbl followed by Apo2L/TRAIL induced apoptosis in Apo2L/TRAIL-resistant tumor cells, characterized by cleavage of caspase-3, caspase-8, and PARP. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of IB and inhibition of NF-B DNA binding activity. NO-Cbl suppressed Apo2L/TRAIL- and TNF--mediated activation of a transfected NF-B-driven luciferase reporter. XIAP, an inhibitor of apoptosis, was inactivated by NO-Cbl. NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of NO-Cbl and Apo2L/TRAIL capitalizes on the tumor-specific properties of both agents and represents a promising anti-cancer combination.
Received for publication, June 10, 2003 , and in revised form, July 23, 2003.
* These studies were supported by the American Cancer Society, Ethicon Endosurgery, CCF Innovations, the Taussig Cancer Center Bridge Grant Program, and National Institutes of Health (to A. A.) Grants CA 81504 and CA 82858. 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.
Both authors contributed equally to this work.
|| To whom correspondence should be addressed: 9500 Euclid Ave., R40 Cleveland, OH 44195. Tel.: 216-445-0548; Fax: 216-636-2498; E-mail: lindned{at}cc.ccf.org.
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