Prevention of colorectal carcinogenesis by DNA-binding small-molecule curaxin CBL0137 involves suppression of Wnt signaling

Chemoprevention is considered a valid approach to reduce the incidence of colorectal cancer, one of the most common malignancies worldwide. Here, we investigated the tumor-preventive activity of curaxin CBL0137. This compound represents a new class of nonmutagenic DNA-binding small molecules that alter chromatin stability and inhibit the function of the histone chaperone FACT. Among downstream effects of CBL0137 treatment are activation of p53 and type I interferons and inhibition of NFkB, HSF1, and MYC. In addition, our data show that in both human and mouse colorectal cancer cells in vitro, CBL0137 inhibits the APC/WNT/b-catenin signaling pathway, which plays a key role in colon carcinogenesis. Using quantitative RT-PCR and microarray hybridization, we have demonstrated decreased expression of multiple components and downstream targets of the WNT pathway in colon cancer cells treated with CBL0137. At the same time, CBL0137 induced expression of WNT antagonists. Inhibition of WNT signaling activity by CBL0137 was also confirmed by luciferase reporter assay. Tumor-preventive activity of CBL0137 in vivo was tested in a murine model of colorectal carcinogenesis induced by 1,2-dimethylhydrazine (DMH), which is known to involve WNT pathway dysregulation. After DMH subcutaneous treatment, mice were administered CBL0137 in drinking water. Efficacy of CBL0137 in suppressing development of colorectal cancer in this model was evidenced by reduced incidence of adenocarcinomas and adenomas in both males and females and decrease in tumor multiplicity. These data support the prospective use of CBL0137 in chemoprevention of colorectal cancer as well as of other malignances associated with activated WNT signaling. © 2019 American Association for Cancer Research.

Kirsanov K. 1, 2 , Fetisov T.1 , Lesovaya E.A.1, 3 , Maksimova V.1 , Trukhanova L.1 , Antoshina E.1 , Gor'kova T.1 , Morozova O.1 , Safina A. 4 , Fleyshman D.4 , Salimov R.5 , Shipaeva E.5 , Ivanov R.5 , Leonov A.5 , Purmal A.A.4 , Belitsky G.A.1 , Gudkov A.V.4 , Gurova K.V.4 , Yakubovskaya M.G.1, 6
American Association for Cancer Research Inc.
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  • 1 N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation
  • 2 RUDN University, Moscow, Russian Federation
  • 3 Ryazansky State Medical University, Ryazan, Russian Federation
  • 4 Roswell Park Cancer Institute, Buffalo, NY, United States
  • 5 Incuron, LLC, Moscow, Russian Federation
  • 6 N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe shosse 24, Moscow, 115478, Russian Federation
1,2 dimethylhydrazine; APC protein; beta catenin; cbl 0137; heat shock transcription factor 1; interferon; Myc protein; protein inhibitor; unclassified drug; Wnt protein; animal cell; animal experiment; animal model; animal tissue; Article; colon carcinogenesis; colorectal cancer; controlled study; cytotoxicity; drug efficacy; enzyme inhibition; enzyme repression; human; human cell; in vitro study; in vivo study; luciferase assay; microarray analysis; mouse; nonhuman; priority journal; prospective study; protein expression; protein targeting; real time polymerase chain reaction; Wnt signaling
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