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2018-Miyazaki et al-Selective cytotoxicity of dihydroorotate dehydrogenase inhibitors to human cancer cells.pdf (2.22 MB)

Selective cytotoxicity of dihydroorotate dehydrogenase inhibitors to human cancer cells under hypoxia and nutrient-deprived conditions

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posted on 2023-06-09, 15:25 authored by Yuki Miyazaki, Daniel Inaoka, Tomoo Shiba, Hiroyuki Saimoto, Takaya Sakura, Eri Amalia, Yasutoshi Kido, Chika Sakai, Mari Nakamura, Anthony Moore, Shigeharu Harada, Kiyoshi Kita
Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure–activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment.

History

Publication status

  • Published

File Version

  • Published version

Journal

Frontiers in Pharmacology

ISSN

1663-9812

Publisher

Frontiers Media

Issue

997

Volume

9

Page range

1-13

Department affiliated with

  • Biochemistry Publications

Research groups affiliated with

  • Behavioural and Clinical Neuroscience Research Group Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-10-09

First Open Access (FOA) Date

2018-10-09

First Compliant Deposit (FCD) Date

2018-10-09

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