DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes
| Autor: | Atsushi Iwama, Motohiko Oshima, Koutaro Yokote, Satoshi Kaito, Daisuke Shinoda, William Joseph Lennox, Yurie Nagai, Emiko Sakaida, Wakako Kuribayashi, Josephine Sheedy, Marla Weetall, Shuhei Koide, Naoya Mimura, Yaeko Nakajima-Takagi, Kiyoko Izawa, Masayuki Yamashita, Atsushi Miyawaki, Satoshi Yamazaki, Kensuke Kayamori, Hans Jiro Becker, Kaoru Tohyama, Ryoji Ito, Satoshi Iwano, Cheng Zhong |
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| Rok vydání: | 2021 |
| Předmět: |
Oxidoreductases Acting on CH-CH Group Donors
Myeloid Neoplasia Chemistry Dihydroorotate Dehydrogenase Myeloid leukemia Decitabine Cytidine DNA Hematology Transfection Mice chemistry.chemical_compound Cell culture Myelodysplastic Syndromes hemic and lymphatic diseases Pyrimidine metabolism Dihydroorotate dehydrogenase medicine Cancer research Animals Cytotoxic T cell medicine.drug |
| Zdroj: | Blood Adv |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS. |
| Databáze: | OpenAIRE |
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