期刊
ONCOTARGET
卷 8, 期 56, 页码 96062-96078出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.21708
关键词
auranofin; tumour drug resistance; human tumour cell lines; drug effects; gene expression
资金
- Associazione Italiana per la Ricerca sul Cancro, Milan [AIRC-IG16049, 15565]
- Istituto Toscano Tumori (Messori-ITT)
- Ente Cassa di Risparmio di Firenze, Florence [2014/0706, 2014/0969]
- Associazione Giacomo Onlus, Castiglioncello
The anti-arthritic drug auranofin exerts also potent antitumour activity in in vitro and in vivo models, whose mechanisms are not yet well defined. From an auranofinsensitive human ovarian cancer cell line A2780, a highly resistant (>20-fold) subline (A2780/AF-R) was developed and characterized. Marked reduction of gold accumulation occurred in auranofin-resistant A2780 cells. Also, moderately higher thioredoxin reductase activity in A2780/AF-R cells was observed while no changes in intracellular glutathione content occurred. Resistance to auranofin was associated with a low level of cross-resistance to some investigational gold compounds as well as to oxaliplatin and other anticancer drugs with different mode of action (i.e. melphalan, vinblastine, doxorubicin, etoposide, and paclitaxel). Reduced gold accumulation was associated to substantial gene expression changes in various influx (e.g. SLC22A1, SLC47A1, SLCO1B1) and efflux (e.g. ABCB1, ABCC2, ABCC3) transporters. The expression levels of selected proteins (i.e. SLC22A1, SLC47A1, P-gp) were also changed accordingly. These data provide evidence that multiple drug transporters may act as mediators of transport of auranofin and other gold compounds in cancer cells. Further investigation into the molecular mechanisms mediating transport of auranofin and new gold complexes in view of their potential clinical application in the treatment of cancer is warranted.
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