HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Increased mitochondrial DNA copy-number in CEM cells resistant to delayed toxicity of 2',3'-dideoxycytidine.

Abstract
The nucleoside analog 2',3'-dideoxycytidine (ddC) has been used for treatment of human immunodeficiency virus (HIV) infections. ddC causes delayed toxicity when cells are exposed to the drug at low concentration for prolonged periods of time. The delayed toxicity is due to inhibition of mitochondrial DNA (mtDNA) replication, which results in mtDNA depletion and mitochondrial dysfunction. In the present study we have cultured CEM T-lymphoblast cells in the presence of low concentrations of ddC to generate two cell lines resistant to the delayed toxicity of the drug. Both cell lines were resistant to mtDNA depletion by ddC. The mechanism of ddC resistance was investigated and we showed that the resistant cells had decreased mRNA expression of the nucleoside kinases deoxycytidine kinase and thymidine kinase 2. We also studied the mitochondrial DNA in the cells and showed that the ddC-resistant cells had structurally intact mtDNA but 1.5-2-fold increased mtDNA copy-number as well as increased levels of the mitochondrial transcription factor A (Tfam). Our study suggests that cells may increase their level of mtDNA to counteract mtDNA depletion induced by ddC, while keeping pronounced antiviral activity of the drug.
AuthorsMia Bjerke, Maribel Franco, Magnus Johansson, Jan Balzarini, Anna Karlsson
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 75 Issue 6 Pg. 1313-21 (Mar 15 2008) ISSN: 1873-2968 [Electronic] England
PMID18206854 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-HIV Agents
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • RNA, Messenger
  • Reverse Transcriptase Inhibitors
  • SLC25A19 protein, human
  • TFAM protein, human
  • Transcription Factors
  • Zalcitabine
  • Adenosine Triphosphate
  • thymidine kinase 2
  • Thymidine Kinase
  • thymidine kinase 1
  • Deoxycytidine Kinase
Topics
  • Adenosine Triphosphate (metabolism)
  • Anti-HIV Agents (toxicity)
  • Cell Line, Tumor
  • DNA, Mitochondrial (metabolism)
  • DNA-Binding Proteins (metabolism)
  • Deoxycytidine Kinase (genetics)
  • Drug Resistance
  • Gene Expression Profiling
  • Humans
  • Membrane Transport Proteins (genetics)
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins (metabolism)
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger (metabolism)
  • Reverse Transcriptase Inhibitors (toxicity)
  • Thymidine Kinase (genetics)
  • Transcription Factors (metabolism)
  • Zalcitabine (toxicity)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: