In vitro and in vivo efficacy of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on human melanoma |
| |
Authors: | Francesca Pellizzari Tregno Andrea Sau Silvia Pezzola Cristina Geroni Caterina Lapenta Massimo Spada Giuseppe Filomeni Elena Bonanno Giorgio Federici Anna Maria Caccuri |
| |
Affiliation: | 1. Department of Clinical Medicine Insubria University, Varese, Italy;2. Department of Clinical Medicine and Surgery, Regional Reference Centre for Coagulation Disorders, "Federico II" University, Naples, Italy;3. Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy;1. Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China;2. Oncology Department, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China;1. Department of Pediatric Hematology, Gulhane Military Academy of Medicine, Ankara, Turkey;2. Regional Blood Center of Gulhane Military Academy of Medicine, Ankara, Turkey;3. Department of Infectious Disease and Clinical Microbiology, Gulhane Military Academy of Medicine Haydarpasa Training Hospital, Istanbul, Turkey;4. Department of General Surgery, Gulhane Military Academy of Medicine, Ankara, Turkey;5. Department of Immunology and Allergic Disease, Gulhane Military Academy of Medicine, Ankara, Turkey;6. Department of Department of Biostatistics, Gulhane Military Academy of Medicine, Ankara, Turkey;7. Department of Infectious Disease and Clinical Microbiology, Gulhane Military Academy of Medicine, Ankara, Turkey |
| |
Abstract: | 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) is a powerful inhibitor of the glutathione transferase P1-1 (GSTP1-1) and causes the disruption of the complex between GSTP1-1 and c-Jun N-terminal Kinase (JNK). This induces JNK activation and apoptosis in tumour cells. In the present work we assess the in vitro and in vivo effectiveness of NBDHEX on two human melanoma cell lines, Me501 and A375. NBDHEX shows IC50 values in the low micromolar range (IC50 of 1.2 ± 0.1 μM and 2.0 ± 0.2 μM for Me501 and A375, respectively) and is over 100 times more cytotoxic to these cell lines than temozolomide. Apoptosis is observed in Me501 cells within 3 h of the addition of NBDHEX, while in A375 cells the apoptotic event is rather late, and is preceded by a G2/M phase arrest. In both melanoma cell lines, JNK activity is required for the ability of NBDHEX to trigger apoptosis, confirming that the JNK pathway is an important therapeutic target for this tumour. NBDHEX is also both effective and well tolerated in in vivo tumour models. A tumour inhibition of 70% is observed in vivo against Me501 human melanoma and a similar result is obtained on A375 model, with 63% of tumour inhibition. These findings indicate that the activation of the JNK pathway, through a selective GSTP1-1 targeting, could prove to be a promising new strategy for treating melanoma, which responds poorly to conventional therapies. |
| |
Keywords: | NBDHEX (6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol) Melanoma JNK (c-Jun N-Terminal Kinase) GSTP1-1 (Glutathione S-transferase Pi) Antitumour drug |
本文献已被 ScienceDirect 等数据库收录! |
|