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Zidovudine impairs adipogenic differentiation through inhibition of clonal expansion.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2008 Aug; Vol. 52 (8), pp. 2882-9. Date of Electronic Publication: 2008 May 12. - Publication Year :
- 2008
-
Abstract
- Lipoatrophy is a prevalent side effect of treatment with thymidine analogues. We wished to confine the time point of the antiadipogenic effect of zidovudine (AZT) during adipogenesis and to evaluate the antiproliferative effect of AZT on adipocyte homeostasis. We investigated the effects of AZT on adipogenesis in 3T3-F442A cells and studied their proliferation, differentiation, viability, and adiponectin expression. Cells were exposed to AZT (1 microM, 3 microM, 6 microM, and 180 microM), stavudine (d4T; 3 microM), or dideoxycytosine (ddC; 0.1 microM) for up to 15 days. Differentiation was assessed by real-time PCR and quantification of triglyceride accumulation. Proliferation and clonal expansion were determined by a [(3)H]thymidine incorporation assay. When they were induced to differentiate in the presence of AZT at the maximum concentration in plasma (C(max)) and lower concentrations, 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol and failed to express normal levels of the later adipogenic transcription factors, CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. AZT exerted an inhibitory effect on the completion of the mitotic clonal expansion, which resulted in incomplete 3T3-F442A differentiation and, finally, a reduction in the level of adiponectin expression. In addition, AZT impaired the constitutive proliferation in murine and primary human subcutaneous preadipocytes. In contrast, incubation with d4T and ddC at the C(max) did not affect either preadipocyte proliferation or clonal expansion and differentiation. We conclude that the antiproliferative and antiadipogenetic effects of AZT on murine and primary human preadipocytes reveal the impact of the drug on fat tissue regeneration. These effects of the drug are expected to contribute to disturbed adipose tissue homeostasis and to be influenced by differential drug concentration and penetration in individual patients.
- Subjects :
- 3T3 Cells
Adipocytes cytology
Adipocytes metabolism
Adipogenesis genetics
Animals
CCAAT-Enhancer-Binding Protein-alpha genetics
CCAAT-Enhancer-Binding Protein-beta genetics
Cell Differentiation genetics
Cell Proliferation drug effects
Cells, Cultured
Gene Expression drug effects
Humans
Mice
PPAR gamma genetics
Reverse Transcriptase Inhibitors pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Stavudine pharmacology
Triglycerides metabolism
Adipocytes drug effects
Adipogenesis drug effects
Cell Differentiation drug effects
Zidovudine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 52
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 18474584
- Full Text :
- https://doi.org/10.1128/AAC.01505-07