title: The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma.
abstract: First line treatment of metastatic melanoma includes the methylating agent dacarbazine or its analogue temozolomide (TMZ) with improved pharmacokinetics and tolerability. However, the prognosis of the metastatic disease is poor and several trials are evaluating TMZ in polychemotherapy protocols. The novel glutathione transferase P1-1 (GSTP1-1) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has recently shown activity against melanoma through c-Jun N-terminal kinase activation. In this study we have investigated the in vitro and in vivo efficacy of NBDHEX and TMZ combination against melanoma. The results indicated that NBDHEX and TMZ exerted in vitro synergistic anti-proliferative effects in murine B16 and human A375 melanoma cells. In B16 cells TMZ as single agent caused cell accumulation at the G(2)/M phase of cell cycle, whereas NBDHEX induced mainly apoptotic effects. NBDHEX provoked a higher level of p53 phosphorylation with respect to TMZ and the drug combination caused a more than additive increase of p53 activation. The in vivo efficacy of NBDHEX and TMZ has been investigated in an orthotopic B16 model. Treatment with NBDHEX provoked a reduction of tumour growth comparable to that obtained with TMZ, whereas the drug combination significantly increased tumour growth inhibition with respect to the single agents, without worsening TMZ myelotoxicity. Immunohistochemical analysis of tumour grafts revealed a profound reduction of Cyclin D1 and CD31 in all treatment groups; VEGF expression was, instead, markedly decreased only in NBDHEX or NBDHEX and TMZ treated samples. These findings indicate that NBDHEX represents a good candidate for combination therapies including TMZ, offering new perspectives for the treatment of melanoma.
authors.affiliation: Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Tentori
authors.forename: Annalisa Susanna
authors.initials: AS
authors.lastname: Dorio
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Alessia
authors.initials: A
authors.lastname: Muzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Sau
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vernole
authors.forename: Giorgio
authors.initials: G
authors.lastname: Federici
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Caccuri
authors.forename: Grazia
authors.initials: G
authors.lastname: Graziani
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010069:Oxadiazoles / Q000008:administration & dosage*; D000077204:Temozolomide
chemical_list: C528479:6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol; D010069:Oxadiazoles; D003606:Dacarbazine; D005982:Glutathione Transferase; D000077204:Temozolomide