| Autor: |
Yip, Kenneth W., Zhang, Zhan, Sakemura-Nakatsugawa, Noriko, Huang, Jui-Wen, Vu, Nhu Mai, Chiang, Yi-Kun, Lin, Chih-Lung, Kwan, Jennifer Y. Y., Yue, Shijun, Jitkova, Yulia, To, Terence, Zahedi, Payam, Pai, Emil F., Schimmer, Aaron D., Lovell, Jonathan F., Sessler, Jonathan L., Liu, Fei-Fei |
| Předmět: |
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| Zdroj: |
PLoS ONE; Feb2014, Vol. 9 Issue 2, p1-9, 9p |
| Abstrakt: |
Uroporphyrinogen decarboxylase (UROD) catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16), was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM), but did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE) cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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