Journal article
Cellular determinants of resistance to indolocarbazole analogue 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13(β-D-glucopyranosyl)-5H-indolo[2, 3-alpha]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506), a novel potent topoisomerase I inhibitor, in multidrug-resistant human tumor cells
Oncology research, Vol.9(9), pp.485-494
1997
PMID: 9495454
Abstract
Membrane protein-associated alterations in cellular drug accumulation have been recently implicated in resistance to topoisomerase I (TOP-l)-interactive drugs. The present study investigated the cellular determinants of resistance to the indolocarbazole compound NB-506 [6-Af-formylamino-12,13-dihydro-l,ll-dihydroxy-13(/3-D-gIucopyranosyl)5//- indoIo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7(6//)-dione], a structurally novel TOP-I-interactive drug, in parental and multidrug-resistant tumor cells expressing either the P-170 glycoprotein (Pgp°) or multidrug resistance protein (MRP). MRP-expressing 250-fold doxorubicin-resistant human fibrosarcoma HT1080/DR4 tumor cells were drug sensitive to NB-506 and camptothecin (CPT) (resistance factor: 0.7 and 0.8, respectively) with no alterations of TOP-I parameters including DNA relaxation, expression of TOP-1 protein and mRNA. In contrast, doxorubicin-resistant human ovarian A2780/Dx5 tumor cells [Pgp° phenotype] were 6.2-fold resistant to NB-506, whereas resistance to CPT was 2.6-fold. HPLC analysis of cellular NB-506 accumulation showed no significant differences between A2780 and A2780/Dx5 cells (peak intracellular concentrations after 120-min exposure to 10 ^M NB-506: 400 ±85.0 and 352 ±95.1 nmol NB-506/mg protein, respectively). However, resistant A2780/Dx5 cells expressed a lower amout of TOP-I mRNA and 29% protein levels of TOP-I compared to parental A2780 cells, resulting in decreased TOP-I catalytic activity (3.17 ±0.02 vs. 1.16 ±0.15 rel.U/^g nuclear protein) and reduced induction of NB-506-mediated cleavable complex formation in A2780/Dx5 cells. Furthermore, the lower induction of NB-506-induced protein-linked DNA breaks (PLDB) in A2780/Dx5 cells correlated with significantly decreased DNA 12.2-440 kb size fragmentation in these cells. The present study demonstrates that expression of MRP and Pgp° does not confer resistance to NB-506. Resistance to indolocarbazole substance NB-506 in A2780/Dx5 cells was only related to downregulation of TOP-I associated with lower induction of cleavable complex formation and DNA fragmentation. The data reported herein may indicate that the new indolocarbazole compound NB-506 has potent antitumor efficacy in membrane-associated multidrug resistance.
Details
- Title: Subtitle
- Cellular determinants of resistance to indolocarbazole analogue 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13(β-D-glucopyranosyl)-5H-indolo[2, 3-alpha]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506), a novel potent topoisomerase I inhibitor, in multidrug-resistant human tumor cells
- Creators
- U Vanhoefer - Roswell Park Cancer InstituteW Voigt - Roswell Park Cancer InstituteR. A Hilger - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, 45122 Essen, GermanyM.-B Yin - Roswell Park Cancer InstituteA Harstrick - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, 45122 Essen, GermanyS Seeber - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, 45122 Essen, GermanyY. M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Oncology research, Vol.9(9), pp.485-494
- Publisher
- Pergamon Press
- PMID
- 9495454
- ISSN
- 0965-0407
- eISSN
- 1555-3906
- Language
- English
- Date published
- 1997
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359838402771
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