| RRC ID |
76966
|
| 著者 |
Kawatani M, Aono H, Hiranuma S, Shimizu T, Muroi M, Nogawa T, Ohishi T, Ohba SI, Kawada M, Yamazaki K, Dan S, Dohmae N, Osada H.
|
| タイトル |
Identification of a dihydroorotate dehydrogenase inhibitor that inhibits cancer cell growth by proteomic profiling.
|
| ジャーナル |
Oncol Res
|
| Abstract |
Dihydroorotate dehydrogenase (DHODH) is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases. This study presents the identification of a potent DHODH inhibitor by proteomic profiling. Cell-based screening revealed that NPD723, which is reduced to H-006 in cells, strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells. H-006 also suppressed the growth of various cancer cells. Proteomic profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors. H-006 potently inhibited human DHODH activity in vitro, whereas NPD723 was approximately 400 times less active than H-006. H-006-induced cell death was rescued by the addition of the DHODH product orotic acid. Moreover, metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic acid. These results suggest that NPD723 is reduced in cells to its active metabolite H-006, which then targets DHODH and suppresses cancer cell growth. Thus, H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.
|
| 巻・号 |
31(6)
|
| ページ |
833-844
|
| 公開日 |
2023-1-1
|
| DOI |
10.32604/or.2023.030241
|
| PII |
30241
|
| PMID |
37744270
|
| PMC |
PMC10513951
|
| MeSH |
Cell Cycle
Cell Death
Cell Transformation, Neoplastic
Dihydroorotate Dehydrogenase*
Humans
Proteomics*
|
| IF |
4.949
|
| リソース情報 |
| ヒト・動物細胞 |
WI-38
K562(RCB0027)
1C3D3(RCB0796)
MCF7(RCB1904)
MIA Paca2(RCB2094)
HL-60
Jurkat
HeLa
A549
Hep G2
A431 |
