2. Academic Validation
  3. Identification of Monobenzone as a Novel Potential Anti-Acute Myeloid Leukaemia Agent That Inhibits RNR and Suppresses Tumour Growth in Mouse Xenograft Model

Identification of Monobenzone as a Novel Potential Anti-Acute Myeloid Leukaemia Agent That Inhibits RNR and Suppresses Tumour Growth in Mouse Xenograft Model

  • Cancers (Basel). 2022 Sep 27;14(19):4710. doi: 10.3390/cancers14194710.
Jingwen Dong 1 2 3,  Tingting Zhong 4,  Zhijian Xu 5,  Haiyi Chen 6,  Xianjun Wang 1,  Lili Yang 1,  Zhiyuan Lou 1,  Yuanling Xu 1,  Tingjun Hou 6,  Rongzhen Xu 1 2 3,  Weiliang Zhu 5,  Jimin Shao 1 2 3
Affiliations

Affiliations

  • 1 Department of Pathology and Pathophysiology, Cancer Institute of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310005, China.
  • 2 Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, School of Medicine, Zhejiang University, Hangzhou 310030, China.
  • 3 Cancer Center, Zhejiang University, Hangzhou 310030, China.
  • 4 Department of Pathology of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310020, China.
  • 5 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 310063, China.
  • 6 Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310030, China.
PMID: 36230632 DOI: 10.3390/cancers14194710
Abstract

Acute myeloid leukaemia (AML) is one of the most common types of haematopoietic malignancy. Ribonucleotide reductase (RNR) is a key Enzyme required for DNA synthesis and cell proliferation, and its small subunit RRM2 plays a key role for the enzymatic activity. We predicted monobenzone (MB) as a potential RRM2 target compound based on the crystal structure of RRM2. In vitro, MB inhibited recombinant RNR activity (IC50 = 0.25 μM). Microscale thermophoresis indicated that MB inhibited RNR activity by binding to RRM2. MB inhibited cell proliferation (MTT IC50 = 6-18 μM) and caused dose-dependent DNA synthesis inhibition, cell cycle arrest, and Apoptosis in AML cells. The cell cycle arrest was reversed by the addition of deoxyribonucleoside triphosphates precursors, suggesting that RNR was the intracellular target of the compound. Moreover, MB overcame drug resistance to the common AML drugs cytarabine and doxorubicin, and treatment with the combination of MB and the Bcl-2 Inhibitor ABT-737 exerted a synergistic inhibitory effect. Finally, the nude mice xenografts study indicated that MB administration produced a significant inhibitory effect on AML growth with relatively weak toxicity. Thus, we propose that MB has the potential as a novel anti-AML therapeutic agent in the future.

Keywords

acute myeloid leukaemia; anti-proliferative activity; combination therapy; monobenzone; ribonucleotide reductase.

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