The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells
Open Access
- 15 July 2005
- journal article
- Published by American Society of Hematology in Blood
- Vol. 106 (2), 698-705
- https://doi.org/10.1182/blood-2004-11-4286
Abstract
Melphalan, a DNA cross-linker, is one of the most widely used and effective drugs in the treatment of multiple myeloma (MM). In this report, we demonstrate that enhanced interstrand cross-link (ICL) repair via the Fanconi anemia (FA)/BRCA pathway contributes to acquired drug resistance in melphalan-resistant myeloma cell lines, and disruption of this pathway reverses drug resistance. Using the alkaline comet assay (single-cell gel electrophoresis), we observed that melphalan-resistant cells have reduced ICL formation and enhanced ICL repair compared with melphalan-sensitive cells. Cell-cycle studies demonstrated that enhanced ICL repair released cells from melphalan-induced cell-cycle delay. Using siRNA to knock down FANCF in 8226/LR5 and U266/LR6 drug-resistant cells demonstrated a direct relationship between ICL repair capacity and drug sensitivity. Overexpression of FANCF in 8226/S and U266/S drug-sensitive cells partially reproduced the drug-resistant phenotype. These data show that enhanced DNA repair via the Fanconi anemia/BRCA pathway is involved in acquired melphalan resistance. Our findings provide for a new target to enhance response to DNA cross-linking agents in cancer treatment. (Blood. 2005;106:698-705)This publication has 47 references indexed in Scilit:
- A Role for the Fanconi Anemia C Protein in Maintaining the DNA Damage-induced G2 CheckpointOnline Journal of Public Health Informatics, 2004
- X-linked inheritance of Fanconi anemia complementation group BNature Genetics, 2004
- The Fanconi Anemia Gene Product FANCF Is a Flexible Adaptor ProteinOnline Journal of Public Health Informatics, 2004
- Recombination repair pathway in the maintenance of chromosomal integrity against DNA interstrand crosslinksCytogenetic and Genome Research, 2004
- Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survivalOncogene, 2003
- A novel ubiquitin ligase is deficient in Fanconi anemiaNature Genetics, 2003
- Disruption of the Fanconi anemia–BRCA pathway in cisplatin-sensitive ovarian tumorsNature Medicine, 2003
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Expression cloning of a cDNA for the major Fanconi anaemia gene, FAANature Genetics, 1996
- Alkylation of DNA by melphalan with special reference to adenine derivatives and adenine-guanine cross-linkingChemico-Biological Interactions, 1993