The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4- ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma

Lucio Tentori, Annalisa Susanna Dorio, Emanuela Mazzon, Alessia Muzi, Andrea Sau, Salvatore Cuzzocrea, Patrizia Vernole, Giorgio Federici, Anna Maria Caccuri, Grazia Graziani

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)1219-1230
Number of pages12
JournalEuropean Journal of Cancer
Issue number8
Publication statusPublished - May 2011



  • Chemotherapy
  • Drug resistance
  • Glutathione transferase inhibitors
  • Melanoma
  • Methylating agents

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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