期刊
ONCOTARGET
卷 7, 期 10, 页码 11664-11676出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7345
关键词
pirinixic acid derivative; ABCB1; cancer; drug resistance; pirinixic acid
资金
- Hilfe fur krebskranke Kinder Frankfurt e.V.
- Frankfurter Stiftung fur krebskranke Kinder
- Kent Cancer Trust
Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPAR alpha, PPAR gamma, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPAR alpha, and PPAR gamma represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPAR alpha, or PPAR gamma. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2 mu M with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
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