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Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells.
- Source :
-
British journal of haematology [Br J Haematol] 2006 Oct; Vol. 135 (1), pp. 52-61. Date of Electronic Publication: 2006 Aug 22. - Publication Year :
- 2006
-
Abstract
- Ribonucleotide reductase (RR) is the enzyme that catalyses the rate-limiting step in DNA synthesis, the production of deoxynucleotides. RR activity is markedly elevated in tumour tissue and is crucial for cell division. It is therefore an excellent target for cancer chemotherapy. This study examined the anti-myeloma activity of Didox (3,4-Dihydroxybenzohydroxamic acid), a novel RR inhibitor (RRI). Our data showed that Didox induced caspase-dependent multiple myeloma (MM) cell apoptosis. Didox, unlike other RRIs that mainly target the pyrimidine metabolism pathway, targets both purine and pyrimidine metabolism pathways in MM, as demonstrated by transcriptional profiling using the Affymetrix U133A 2.0 gene chip. Specifically, a >or=2-fold downregulation of genes in these anabolic pathways was shown as early as 12 h after exposure to Didox. Furthermore, apoptosis was accompanied by downregulation of bcl family proteins including bcl-2, bcl(xl), and XIAP. Importantly, RR M1 component transcript was also downregulated, associated with decreased protein expression. Genes involved in DNA repair mechanisms, specifically RAD 51 homologue, were also downregulated. As Didox acts on MM cells by inhibiting DNA synthesis and repair, combination studies with melphalan, an agent commonly used in MM, were performed. A strong in vitro synergism was shown, with combination indices of <0.7 as determined by the Chou-Talalay method. These studies therefore provide the preclinical rationale for evaluation of Didox, alone and in combination with DNA-damaging agents, to improve patient outcome in MM.
- Subjects :
- Antineoplastic Agents, Alkylating pharmacology
Caspases physiology
Cell Cycle drug effects
Cell Survival drug effects
DNA Repair genetics
Dose-Response Relationship, Drug
Down-Regulation drug effects
Drug Evaluation, Preclinical
Drug Synergism
Enzyme Inhibitors pharmacology
Gene Expression Regulation, Neoplastic drug effects
Humans
Melphalan pharmacology
Multiple Myeloma genetics
Multiple Myeloma metabolism
Neoplasm Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Ribonucleotide Reductases antagonists & inhibitors
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Apoptosis drug effects
DNA Repair drug effects
Hydroxamic Acids pharmacology
Multiple Myeloma pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1048
- Volume :
- 135
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 16925573
- Full Text :
- https://doi.org/10.1111/j.1365-2141.2006.06261.x