title: Azidothymidine is effective against human multiple myeloma: a new use for an old drug?
abstract: 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.
authors.affiliation: Laboratory of Genetics and Molecular Hematology, LIM 31, University of São Paulo School of Medicine, São Paulo, Brazil. julianapereira29@hotmail.com
authors.forename: Juliana
authors.initials: J
authors.lastname: Pereira
authors.forename: Débora
authors.initials: D
authors.lastname: Levy
authors.forename: Jorge L M
authors.initials: JL
authors.lastname: Ruiz
authors.forename: Graciela A
authors.initials: GA
authors.lastname: Brocardo
authors.forename: Kleber A
authors.initials: KA
authors.lastname: Ferreira
authors.forename: Renata O
authors.initials: RO
authors.lastname: Costa
authors.forename: Rodrigo G
authors.initials: RG
authors.lastname: Queiroz
authors.forename: Durvanei A
authors.initials: DA
authors.lastname: Maria
authors.forename: Abrahao E Hallack
authors.initials: AE
authors.lastname: Neto
authors.forename: Dalton A F
authors.initials: DA
authors.lastname: Chamone
authors.forename: Sérgio P
authors.initials: SP
authors.lastname: Bydlowski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D015215:Zidovudine