Azidothymidine is Effective Against Human Multiple Myeloma: A New Use for an Old Drug?
Jorge L.M. Ruiz,
Graciela A. Brocardo,
Kleber A. Ferreira,
Renata O. Costa,
Rodrigo G. Queiroz,
Durvanei A. Maria,
Abrahao E. Hallack Neto,
Dalton A.F. Chamone,
Sergio P. Bydlowski.
Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-κB pathway. As multiple
myeloma (MM) presents with constitutive activation of NF-κB, 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) or resistant to doxorubicin (8226/DX5) and human T cell
lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicity was also evaluated in vivo in nude mice
xenografted with 8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and
the NF-κB pathway was analyzed in the xenografts using real-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 to untreated mice (p = 0.0003). AZT down-regulated the pro-proliferative
genes encoding AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2; pro-angiogenenic genes encoding VEGF and
IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF-κB pathway. AZT up-regulated the expression of tumor
suppressor gene FOXP1 and 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.
Keywords: Multiple myeloma, Zidovudine, Cell proliferation, Apoptosis, Angiogenesis, Cytotoxic, Trizol, bortezomib, NF-kB/2, FOXP1
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