DHS (trans−4,4′-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2)

Chi Wei Chen, Yongming Li, Shuya Hu, Wei Zhou, Yunxiao Meng, Zongzhu Li, Yi Zhang, Jing Sun, Zhou Bo, Melvin L. DePamphilis, Yun Yen, Zhiyong Han, Wenge Zhu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

DNA replication machinery is responsible for accurate and efficient duplication of the chromosome. Since inhibition of DNA replication can lead to replication fork stalling, resulting in DNA damage and apoptotic death, inhibitors of DNA replication are commonly used in cancer chemotherapy. Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the biosynthesis of deoxyribonucleoside triphosphates (dNTPs) that are essential for DNA replication and DNA damage repair. Gemcitabine, a nucleotide analog that inhibits RNR, has been used to treat various cancers. However, patients often develop resistance to this drug during treatment. Thus, new drugs that inhibit RNR are needed to be developed. In this study, we identified a synthetic analog of resveratrol (3,5,4′-trihydroxy-trans-stilbene), termed DHS (trans−4,4′-dihydroxystilbene), that acts as a potent inhibitor of DNA replication. Molecular docking analysis identified the RRM2 (ribonucleotide reductase regulatory subunit M2) of RNR as a direct target of DHS. At the molecular level, DHS induced cyclin F-mediated down-regulation of RRM2 by the proteasome. Thus, treatment of cells with DHS reduced RNR activity and consequently decreased synthesis of dNTPs with concomitant inhibition of DNA replication, arrest of cells at S-phase, DNA damage, and finally apoptosis. In mouse models of tumor xenografts, DHS was efficacious against pancreatic, ovarian, and colorectal cancer cells. Moreover, DHS overcame both gemcitabine resistance in pancreatic cancer and cisplatin resistance in ovarian cancer. Thus, DHS is a novel anti-cancer agent that targets RRM2 with therapeutic potential either alone or in combination with other agents to arrest cancer development.

Original languageEnglish
JournalOncogene
DOIs
Publication statusPublished - Mar 2019
Externally publishedYes

Fingerprint

Ribonucleotide Reductases
DNA Replication
gemcitabine
Growth
Deoxyribonucleosides
DNA Damage
Neoplasms
Pancreatic Neoplasms
Ovarian Neoplasms
Molecular Docking Simulation
Chromosome Duplication
Stilbenes
Cyclins
Proteasome Endopeptidase Complex
S Phase
Drug Resistance
Heterografts
DNA Repair
Cisplatin
ribonucleotide reductase M2

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

DHS (trans−4,4′-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2). / Chen, Chi Wei; Li, Yongming; Hu, Shuya; Zhou, Wei; Meng, Yunxiao; Li, Zongzhu; Zhang, Yi; Sun, Jing; Bo, Zhou; DePamphilis, Melvin L.; Yen, Yun; Han, Zhiyong; Zhu, Wenge.

In: Oncogene, 03.2019.

Research output: Contribution to journalArticle

Chen, Chi Wei ; Li, Yongming ; Hu, Shuya ; Zhou, Wei ; Meng, Yunxiao ; Li, Zongzhu ; Zhang, Yi ; Sun, Jing ; Bo, Zhou ; DePamphilis, Melvin L. ; Yen, Yun ; Han, Zhiyong ; Zhu, Wenge. / DHS (trans−4,4′-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2). In: Oncogene. 2019.
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abstract = "DNA replication machinery is responsible for accurate and efficient duplication of the chromosome. Since inhibition of DNA replication can lead to replication fork stalling, resulting in DNA damage and apoptotic death, inhibitors of DNA replication are commonly used in cancer chemotherapy. Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the biosynthesis of deoxyribonucleoside triphosphates (dNTPs) that are essential for DNA replication and DNA damage repair. Gemcitabine, a nucleotide analog that inhibits RNR, has been used to treat various cancers. However, patients often develop resistance to this drug during treatment. Thus, new drugs that inhibit RNR are needed to be developed. In this study, we identified a synthetic analog of resveratrol (3,5,4′-trihydroxy-trans-stilbene), termed DHS (trans−4,4′-dihydroxystilbene), that acts as a potent inhibitor of DNA replication. Molecular docking analysis identified the RRM2 (ribonucleotide reductase regulatory subunit M2) of RNR as a direct target of DHS. At the molecular level, DHS induced cyclin F-mediated down-regulation of RRM2 by the proteasome. Thus, treatment of cells with DHS reduced RNR activity and consequently decreased synthesis of dNTPs with concomitant inhibition of DNA replication, arrest of cells at S-phase, DNA damage, and finally apoptosis. In mouse models of tumor xenografts, DHS was efficacious against pancreatic, ovarian, and colorectal cancer cells. Moreover, DHS overcame both gemcitabine resistance in pancreatic cancer and cisplatin resistance in ovarian cancer. Thus, DHS is a novel anti-cancer agent that targets RRM2 with therapeutic potential either alone or in combination with other agents to arrest cancer development.",
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AU - Li, Yongming

AU - Hu, Shuya

AU - Zhou, Wei

AU - Meng, Yunxiao

AU - Li, Zongzhu

AU - Zhang, Yi

AU - Sun, Jing

AU - Bo, Zhou

AU - DePamphilis, Melvin L.

AU - Yen, Yun

AU - Han, Zhiyong

AU - Zhu, Wenge

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AB - DNA replication machinery is responsible for accurate and efficient duplication of the chromosome. Since inhibition of DNA replication can lead to replication fork stalling, resulting in DNA damage and apoptotic death, inhibitors of DNA replication are commonly used in cancer chemotherapy. Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the biosynthesis of deoxyribonucleoside triphosphates (dNTPs) that are essential for DNA replication and DNA damage repair. Gemcitabine, a nucleotide analog that inhibits RNR, has been used to treat various cancers. However, patients often develop resistance to this drug during treatment. Thus, new drugs that inhibit RNR are needed to be developed. In this study, we identified a synthetic analog of resveratrol (3,5,4′-trihydroxy-trans-stilbene), termed DHS (trans−4,4′-dihydroxystilbene), that acts as a potent inhibitor of DNA replication. Molecular docking analysis identified the RRM2 (ribonucleotide reductase regulatory subunit M2) of RNR as a direct target of DHS. At the molecular level, DHS induced cyclin F-mediated down-regulation of RRM2 by the proteasome. Thus, treatment of cells with DHS reduced RNR activity and consequently decreased synthesis of dNTPs with concomitant inhibition of DNA replication, arrest of cells at S-phase, DNA damage, and finally apoptosis. In mouse models of tumor xenografts, DHS was efficacious against pancreatic, ovarian, and colorectal cancer cells. Moreover, DHS overcame both gemcitabine resistance in pancreatic cancer and cisplatin resistance in ovarian cancer. Thus, DHS is a novel anti-cancer agent that targets RRM2 with therapeutic potential either alone or in combination with other agents to arrest cancer development.

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