Effects of AZT on cellular iron homeostasis.
3'-azido-3'-deoxythymidine (AZT), the first chemotherapeutic drug approved by FDA for treatment of HIV-infected patients and still used in combination therapy, has been shown to induce, upon prolonged exposure, severe bone marrow toxicity manifested as anemia, neutropenia and siderosis. These toxic effects are caused by inhibition of heme synthesis and, as a consequence, transferrin receptor (TfR) number appears increased and so iron taken up by cells. Since iron overload can promote the frequency and severity of many infections, siderosis is viewed as a further burden for AIDS patients. We have previously demonstrated that AZT-treated K562 cells showed an increase of the number of TfRs located on the surface of the plasma membrane without affecting their biosynthesis, but slowing down their endocytotic pathway. In spite of the higher number of receptors on the plasma-membrane of AZT-treated cells, intracellular accumulation of iron showed a similar level in control and in drug-exposed cells. The chelating ability of AZT and of its phosphorylated derivatives, both in an acellular system and in K562 cells, was also checked. The results demonstrated that AZT and AZTMP were uneffective as iron chelators, while AZTTP displayed a significant capacity to remove iron from transferrin (Tf). Our results suggest that AZT may be not directly involved in the iron overloading observed upon its prolonged use in AIDS therapy. The iron accumulation found in these patients is instead caused by other unknown mechanisms that need further studies to be clarified.
Bozzi
Argante
A
Department of Biomedical Sciences and Technologies, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy. bozzi@cc.univaq.it
Brisdelli
Fabrizia
F
D'Alessandro
Anna M
AM
D'Andrea
Gabriele
G
Lizzi
Anna R
AR
Rinaldi
Andrea C
AC
Oratore
Arduino
A
D000818:Animals; D002477:Cells / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015215:Zidovudine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D015215:Zidovudine; D007501:Iron