Azidothymidine is Effective Against Human Multiple Myeloma: A New Use for an Old Drug?
Carregando...
Citações na Scopus
10
Tipo de produção
article
Data de publicação
2013
Título da Revista
ISSN da Revista
Título do Volume
Editora
BENTHAM SCIENCE PUBL LTD
Autores
RUIZ, Jorge L. M.
FERREIRA, Kleber A.
COSTA, Renata O.
QUEIROZ, Rodrigo G.
MARIA, Durvanei A.
HALLACK NETO, Abrahao E.
Citação
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v.13, n.1, p.186-192, 2013
Resumo
Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-kappa B pathway. As multiple myeloma (MM) presents with constitutive activation of NF-kappa 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) 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-kappa B 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-kappa B 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.
Palavras-chave
Multiple myeloma, Zidovudine, Cell proliferation, Apoptosis, Angiogenesis, Cytotoxic
Referências
- Bazzi M., 2010, CANCER BIOL THER, V23, P830
- Bower M, 1999, AIDS, V13, P2105, DOI 10.1097/00002030-199910220-00014
- Chen SH, 2010, ANTICANCER RES, V30, P4177
- Chow WA, 2009, LANCET ONCOL, V10, P61, DOI 10.1016/S1470-2045(08)70334-6
- DALTON WS, 1986, CANCER RES, V46, P5125
- Fan QW, 2010, SCI SIGNAL, V3, DOI 10.1126/scisignal.2001017
- Ghosh SK, 2003, BLOOD, V101, P2321, DOI 10.1182/blood-2002-08-2525
- Gyrd-Hansen M, 2010, NAT REV CANCER, V10, P561, DOI 10.1038/nrc2889
- Hideshima T, 2001, CANCER RES, V61, P3071
- Humer J, 2008, MELANOMA RES, V18, P314, DOI 10.1097/CMR.0b013e32830aaaa6
- Liu Q, 2003, BLOOD, V101, P4078, DOI 10.1182/blood-2002-10-3231
- Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262
- MITSUYA H, 1985, P NATL ACAD SCI USA, V82, P7096, DOI 10.1073/pnas.82.20.7096
- MOSMANN T, 1983, J IMMUNOL METHODS, V65, P55, DOI 10.1016/0022-1759(83)90303-4
- Nakanishi C, 2005, NAT REV CANCER, V5, P297, DOI 10.1038/nrc1588
- Sailaja G, 1996, BIOCHEM PHARMACOL, V52, P857, DOI 10.1016/0006-2952(96)82183-6
- Solaini G, 2007, BIOSCIENCE REP, V27, P11, DOI 10.1007/s10540-007-9033-4
- van der Meel R, 2011, DRUG DISCOV TODAY, V16, P219, DOI 10.1016/j.drudis.2011.01.005