Effects of interferon β on transcobalamin II-receptor expression and antitumor activity of nitrosylcobalamin

Joseph A. Bauer, Bei H. Morrison, Ronald W. Grane, Barbara S. Jacobs, Sally Dabney, Ana M. Gamero, Kevin A. Carnevale, Daniel J. Smith, Judith Drazba, Bellur Seetharam, Daniel J. Lindner

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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 β (IFN-β) 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-β, 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-β treatment of NIH-OVCAR-3 xenografts induced tumor regression, whereas combination treatment induced tumor eradication. IFN-β 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-β 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-β resulted in enhanced antitumor effects with NO-Cbl both in vitro and in vivo.

Original languageEnglish
Pages (from-to)1010-1019
Number of pages10
JournalJournal of the National Cancer Institute
Volume94
Issue number13
DOIs
StatePublished - Jul 3 2002

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