Azidothymidine is Effective against Human Multiple Myeloma: A New Use for an Old Drug?

Azidothymidine is Effective against Human Multiple Myeloma: A New Use for an Old Drug?

Anticancer Agents Med Chem. 2012 Aug 27;

Authors: Pereira J, Levy D, Ruiz JL, Brocardo GA, Ferreira KA, Costa RO, Queiroz RG, Maria DA, Neto AE, Chamone DA, Bydlowski SP

Abstract
Azidothymidine(AZT)is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-?B pathway. As multiple myeloma (MM)presents with constitutive activation of NF-?B, we analyzed the effect of AZT on human MM cell lines. We evaluated the cytotoxic effect of AZT in human MM cell lines sensitive (8226/S)orresistant to doxorubicin (8226/DX5) and human T cell lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicitywas also evaluated in vivo in nude mice xenografted with an8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and the NF-?B pathway was analyzed in the xenografts usingreal-time polymerase chain reaction.AZT was effective against both 8226/S and 8226/DX5 cells in a dose and time-dependent manner(p = 0.02)in vitro and promoted cell cycle arrest in S phase in these cells. The tumor volume was lower in mice treated with AZT compared tountreated mice (p = 0.0003). AZT down-regulated the pro-proliferative genes encodingAKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2;pro-angiogenenic genes encodingVEGF and IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF-?Bpathway. AZT up-regulated the expression of tumor suppressor gene FOXP1and the pro-apoptotic genes encoding BID, Bcl-10, and caspase-8. Thus, we demonstrated the cytotoxic effect of AZT in human MM cell lines for the first time. Our data may provide the rationale for future clinical trials of AZT for treating MM.

PMID: 22931421 [PubMed - as supplied by publisher]

NF-kB signaling pathway NF-kB pathway NF-kB signaling