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Mol Cancer Ther. 2018 Feb;17(2):497-507. doi: 10.1158/1535-7163.MCT-17-0566. Epub 2017 Dec 27.

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

Author information

1
Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia.
2
Department of Chemistry and Center for Diagnostic and Therapeutics, Georgia State University, Atlanta, Georgia.
3
Department of Chemistry and Center for Diagnostic and Therapeutics, Georgia State University, Atlanta, Georgia. mzhou@emory.edu wang@gsu.edu.
4
Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia. mzhou@emory.edu wang@gsu.edu.
#
Contributed equally

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 self-ubiquitination 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 and MDM2 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. Mol Cancer Ther; 17(2); 497-507. ©2017 AACR.

PMID:
29282301
PMCID:
PMC6054458
DOI:
10.1158/1535-7163.MCT-17-0566
[Indexed for MEDLINE]
Free PMC Article

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