First line treatment of metastatic melanoma includes the methylating agent dacarbazine, which has been replaced in several countries by 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 and apoptosis induction. Methods: In vitro chemosensitivity to the drug combination of B16 melanoma cells was studied by short or long term proliferation assays; apoptosis or cell cycle perturbations were analysed by flow-cytometry, whereas JNK and p53 activation was assessed by immunoblotting. The in vivo toxicity and antitumor efficacy of TMZ and NBDHEX was investigated in an orthotopic B16 model. Immunohistochemical analysis was performed in tumour specimens from treated or untreated animals. Results: Data indicated that NBDHEX and TMZ exerted in vitro synergistic effects. While cell accumulation at the G2/M phase of cell cycle was observed with TMZ, apoptosis prevailed over G2/M arrest when NBDHEX was associated with TMZ. Moreover, NBDHEX provoked a higher level of p53 phosphorylation with respect to TMZ and the drug combination caused a further increase of p53 activation. In vivo treatment with NBDHEX provoked a reduction of tumour growth comparable to that obtained with TMZ, whereas the drug combination significantly increased growth inhibition with respect to the single agents, without worsening TMZ myelotoxicity. Immunohistochemical analysis of tumour grafts revealed a profound reduction of Cyclin D and CD31 in all treatment groups, whereas VEGF expression was markedly decreased in NBDHEX or NBDHEX+TMZ treated samples. Conclusions These findings indicate that NBDHEX represents a good candidate for combination therapies including TMZ, offering new perspectives for the treatment of melanoma.

TENTORI, L., DORIO, A.S., Mazzon, E., MUZI, A., Saua, A., Cuzzocrea, S., et al. (2010). Novel Glutathione S-Transferase Inhibitor Enhances Temozolomide Efficacy Against Malignant Melanoma 52nd Annual Meeting of the Italian Cancer Society. Lost in translation: bridging the gap between cancer research and effective therapies. ??????? it.cilea.surplus.oa.citation.tipologie.CitationProceedings.prensentedAt ??????? Annual Meeting of the Italian Cancer Society. Lost in translation: bridging the gap between cancer research and effective therapies, Roma.

Novel Glutathione S-Transferase Inhibitor Enhances Temozolomide Efficacy Against Malignant Melanoma 52nd Annual Meeting of the Italian Cancer Society. Lost in translation: bridging the gap between cancer research and effective therapies

TENTORI, LUCIO;DORIO, ANNALISA SUSANNA;MUZI, ALESSIA;CACCURI, ANNA MARIA;GRAZIANI, GRAZIA
2010

Abstract

First line treatment of metastatic melanoma includes the methylating agent dacarbazine, which has been replaced in several countries by 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 and apoptosis induction. Methods: In vitro chemosensitivity to the drug combination of B16 melanoma cells was studied by short or long term proliferation assays; apoptosis or cell cycle perturbations were analysed by flow-cytometry, whereas JNK and p53 activation was assessed by immunoblotting. The in vivo toxicity and antitumor efficacy of TMZ and NBDHEX was investigated in an orthotopic B16 model. Immunohistochemical analysis was performed in tumour specimens from treated or untreated animals. Results: Data indicated that NBDHEX and TMZ exerted in vitro synergistic effects. While cell accumulation at the G2/M phase of cell cycle was observed with TMZ, apoptosis prevailed over G2/M arrest when NBDHEX was associated with TMZ. Moreover, NBDHEX provoked a higher level of p53 phosphorylation with respect to TMZ and the drug combination caused a further increase of p53 activation. In vivo treatment with NBDHEX provoked a reduction of tumour growth comparable to that obtained with TMZ, whereas the drug combination significantly increased growth inhibition with respect to the single agents, without worsening TMZ myelotoxicity. Immunohistochemical analysis of tumour grafts revealed a profound reduction of Cyclin D and CD31 in all treatment groups, whereas VEGF expression was markedly decreased in NBDHEX or NBDHEX+TMZ treated samples. Conclusions These findings indicate that NBDHEX represents a good candidate for combination therapies including TMZ, offering new perspectives for the treatment of melanoma.
Annual Meeting of the Italian Cancer Society. Lost in translation: bridging the gap between cancer research and effective therapies
Roma
2010
52.
Rilevanza internazionale
ott-2010
Settore BIO/14
eng
Intervento a convegno
TENTORI, L., DORIO, A.S., Mazzon, E., MUZI, A., Saua, A., Cuzzocrea, S., et al. (2010). Novel Glutathione S-Transferase Inhibitor Enhances Temozolomide Efficacy Against Malignant Melanoma 52nd Annual Meeting of the Italian Cancer Society. Lost in translation: bridging the gap between cancer research and effective therapies. ??????? it.cilea.surplus.oa.citation.tipologie.CitationProceedings.prensentedAt ??????? Annual Meeting of the Italian Cancer Society. Lost in translation: bridging the gap between cancer research and effective therapies, Roma.
Tentori, L; Dorio, As; Mazzon, E; Muzi, A; Saua, A; Cuzzocrea, S; Federici, G; Caccuri, Am; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/42030
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