A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts
| Autor: | De Luca, A, Rotili, D, Carpanese, D, Lenoci, A, Calderan, L, Scimeca, M, Mai, A, Bonanno, E, Rosato, A, Geroni, C, Quintieri, L, Caccuri, Am, DE LUCA, A |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Oral
Administration Oral Apoptosis Human Melanoma Xenografts Pharmacology Settore MED/08 - Anatomia Patologica Cell Line chemistry.chemical_compound Mice Random Allocation c-Jun N-terminal Kinase Animals Cell Line Tumor Cell Proliferation Enzyme Inhibitors Female Glutathione S-Transferase pi Humans Melanoma Oxadiazoles Xenograft Model Antitumor Assays In vivo Settore BIO/10 Glutathione Transferase P1-1 6-((7-nitrobenzo[c][1 2 5]oxadiazoles Tumor Chemistry Cell growth Glutathione In vitro Oncology Cell culture Settore CHIM/09 - Farmaceutico Tecnologico Applicativo Administration Target protein Research Paper |
| Zdroj: | Scopus-Elsevier Europe PubMed Central Oncotarget |
| Popis: | We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC50 in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells. MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations. Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo. |
| Databáze: | OpenAIRE |
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