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Author Notes:

Muxiang Zhou, Division of Hematology/Oncology, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA 30322. Phone: 404-727-1426; Fax: 404-727-4455; mzhou@emory.edu; and Binghe Wang, wang@gsu.edu.

Conception and design: L. Gu, H. Zhang, T. Liu, B. Wang, M. Zhou

Development of methodology: L. Gu, H. Zhang, S. Yi, B. Wang, M. Zhou

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): L. Gu, H. Zhang, T. Liu, A. Draganov, S. Yi

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): L. Gu, H. Zhang, A. Draganov, S. Yi, B. Wang, M. Zhou

Writing, review, and/or revision of the manuscript: A. Draganov, B. Wang, M. Zhou

Administrative, technical, or material support (i.e., reporting or organizing, data, constructing databases): L. Gu, H. Zhang

Study supervision: H. Zhang, B. Wang, M. Zhou

Other (synthesis of the tested compound): A. Draganov

No potential conflicts of interest were disclosed.

Subjects:

Research Funding:

This work was supported by R01 grant (CA180519) to B. Wang and M. Zhou and grants CA123490 and CA143107 to M. Zhou; a research grant (279706) from ST. Baldrick to M. Zhou; and research grants from CURE to M. Zhou and L. Gu.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • ACUTE LYMPHOBLASTIC-LEUKEMIA
  • IN-VIVO
  • P53
  • CELLS
  • PROTEIN
  • DEGRADATION
  • ANTICANCER
  • APOPTOSIS
  • ONCOGENE
  • GENE

Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice

Tools:

Journal Title:

Molecular Cancer Therapeutics

Volume:

Volume 17, Number 2

Publisher:

, Pages 497-507

Type of Work:

Article | Post-print: After Peer Review

Abstract:

A novel small-molecule anthraquinone (AQ) analogue, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a selfubiquitination and proteasome-mediated mechanism. This AQ-101-induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype andMDM2 expression in vitro and in vivo. When given for a period of 2 weeks (20 mg/kg/day, 3/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2.

Copyright information:

© 2017 AACR.

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