© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 13, 1010-1019,
July 3, 2002
© 2002 Oxford University Press
ARTICLE |
Effects of Interferon 
on Transcobalamin II-Receptor Expression and Antitumor Activity of Nitrosylcobalamin
Affiliations of authors: J. A. Bauer, B. H. Morrison, R. W. Grane, B. S. Jacobs, Taussig Cancer Center, Center for Cancer Drug Discovery and Development, The Cleveland Clinic Foundation, Cleveland, OH; S. Dabney, D. J. Smith, Department of Chemistry, The University of Akron, Akron, OH; A. M. Gamero (Department of Immunology), K. A. Carnevale (Department of Cell Biology), J. Drazba (Imaging Core), Lerner Research Institute, The Cleveland Clinic Foundation; B. Seetharam, Division of Gastroenterology and Hepatology, Departments of Medicine and Biochemistry, The Medical College of Wisconsin, Milwaukee; D. J. Lindner, Department of Cancer Biology, Lerner Research Institute, and Taussig Cancer Center, Center for Cancer Drug Discovery and Development, The Cleveland Clinic Foundation.
Correspondence to: D. J. Lindner, M.D., Ph.D., 9500 Euclid Ave., R40, Cleveland, OH 44195 (e-mail: lindned{at}cc.ccf.org).
Background: The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin (Cbl; vitamin B12), an essential micronutrient. Tumors often require more Cbl than normal tissue, and increased Cbl uptake may result from increased TC II-R expression. To examine whether Cbl could therefore be used as a carrier molecule to target a chemotherapy drug, we tested an analogue of Cbl with nitric oxide as a ligand, nitrosylcobalamin (NO-Cbl). Because interferon 
(IFN-) has antitumor effects and increases expression of some membrane receptors, we examined whether it may enhance the effects of NO-Cbl. Methods: Antiproliferative effects of NO-Cbl were assessed in 24 normal and cancer cell lines. Xenograft tumors of human ovarian cancer NIH-OVCAR-3 cells were established in athymic nude mice, and tumor growth was monitored after treatment with NO-Cbl and IFN-, both individually and concomitantly. TC II-R expression and apoptosis was monitored in vitro and in vivo. RNA protection assays and mitochondrial membrane potential assays were used to distinguish the extrinsic and intrinsic apoptotic pathways, respectively. Results: Cancer cell lines were more sensitive to NO-Cbl (with ID50s [the dose that inhibits growth by 50%] as low as 2 µM) than normal cell lines (with ID50s of 85–135 µM). Single-agent NO-Cbl and IFN- treatment of NIH-OVCAR-3 xenografts induced tumor regression, whereas combination treatment induced tumor eradication. IFN- treatment increased TC II-R expression in vitro and uptake of [57Co]cobalamin in vivo. Compared with NIH-OVCAR-3 cells treated with NO-Cbl, cells treated with NO-Cbl and IFN- were more apoptotic and expressed higher mRNA levels of various apoptosis-associated genes. No changes in mitochondrial membrane potential were observed in cells treated with NO-Cbl. Conclusion: NO-Cbl inhibited tumor growth in vivo by activating the extrinsic apoptotic pathway. The increased expression of TC II-R induced by IFN- resulted in enhanced antitumor effects with NO-Cbl both in vitro and in vivo.
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