Antitumor effect of the curaxin CBL0137 on the models of colon cancer

Fetisov, Timur; Тилова, Л Р; Lesovaya, Ekaterina A.; Antoshina, Elena; Gor’kova, Tatiana; Trukhanova, Lubov; Морозова, О. В.; Shipaeva, Elena; Ivanov, R. V.; Purmal, Andrei A.; Belitskiy, G. A.; Yakubovskaya, Marianna G.; Gudkov, Andrei V.; Gurova, Katerina V.; Кирсанов, Кирилл И.

doi:10.17650/2313-805x-2016-3-3-67-72

Cited by 3 publications

(3 citation statements)

References 14 publications

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“…This conclusion is consistent with and further supported by our previously published works showing that CBL0137 has anti-inflammatory effects including COX2 inhibition (20,22), because one of the bioactive products of COX-2 function is prostaglandin E2 that regulates WNT signaling (23). Moreover, CBL0137 was previously shown to activate NOTCH1 expression in small-cell lung cancer, and an interplay between b-catenin signaling and NOTCH1 effectors has been demonstrated in intestinal tumorigenesis (41).…”

Section: Discussionsupporting

confidence: 87%

“…WNT and NFkB signaling pathways have been identified as playing key roles in colon carcinogenesis, and thus they are well recognized as promising drug targets for colorectal cancer prevention and/or treatment (4,12). Inhibition of NFkB by a new class of DNA-binding small molecules (curaxins) represented by CBL0137 has been demonstrated in various colorectal cancer cell lines (20,22). Here, we report for the first time that CBL0137 also inhibits WNT signaling.…”

Section: Discussionmentioning

confidence: 79%

“…Moreover, our recent study revealed CBL0137 influence on type I IFN signaling (19). Using colorectal cancer cell line HCT116, we demonstrated CBL0137 inhibitory effect on COX2 transcription (22). As COX2 catalyzes biosynthesis of prostaglandin E2, which is a known modulator of the WNT pathway, we proposed that CBL0137 might influence WNT signaling pathway (23).…”

Section: Introductionmentioning

confidence: 78%

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Prevention of Colorectal Carcinogenesis by DNA-Binding Small-Molecule Curaxin CBL0137 Involves Suppression of Wnt Signaling

Кирсанов

Fetisov²,

Lesovaya

et al. 2020

Cancer Prevention Research

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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 DNAbinding 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.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 78%

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Prevention of Colorectal Carcinogenesis by DNA-Binding Small-Molecule Curaxin CBL0137 Involves Suppression of Wnt Signaling

Кирсанов

Fetisov²,

Lesovaya

et al. 2020

Cancer Prevention Research

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Anti-cancer activity of сuraxin CBL0137 on the models of acute leukemia in vitro

et al. 2019

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Background. Curaxin CBL0137 is a novel non-genotoxic compound with anti-cancer activity based on CBL0137 ability of non-covalent interaction with DNA causing histone chaperone FACT relocation. Anti-cancer activity of this drug was demonstrated previously on the wide panel of solid cancer models in vitro and in vivo.Objectives. Estimation of anticancer effects of CBL0137 on the acute myeloblastic leukemia cells (THP-1) and acute lymphoblastic leukemia (CCRF-CEM).Materials and methods. CBL0137 cytotoxicity was analyzed using the MTT test, the effects on the cell cycle and the induction of apoptosis was assessed by flow cytometry, the activity of signaling pathways in cells treated with CBL0137 was determined by real-time polymerase chain reaction.Results. Cell treatment with CBL0137 led to cell cycle arrest and apoptosis induction. In the study of CBL0137 effect on target gene clusters of 10 signal transduction pathways involved in the pathogenesis of acute leukemia we have showed that CBL0137 inhibited the expression of down-stream genes of WNT and Hedgehog signaling in both cell lines. In THP-1 cells we also observed the inhibition of the expression of PPARγ target and hypoxia-activated genes. In CCRF-CEM cells CBL0137 also induced the expression of Notch signaling target genes.Conclusion. The antitumor activity of CBL0137 was demonstrated on acute leukemia cell cultures, the drug possesses cytotoxicity, causes cell cycle arrest and activation of apoptosis. Significant changes in the expression of efferent gene clusters of several signaling pathways were observed in the cells treated with CBL0137.

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7-Methylguanine Inhibits Colon Cancer Growth <i>in vivo</i>

Kirsanov,

Fetisov,

Antoshina

et al. 2024

Acta Naturae

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7-Methylguanine (7-MG) is a natural inhibitor of poly(ADP-ribose) polymerase 1 and tRNA-guanine transglycosylase, the enzymatic activity of which is central for the proliferation of cancer cells. Recently, a number of preclinical tests have demonstrated the safety of 7-MG and a regimen of intragastric administration was established in mice. In the present work, the pharmacological activity of 7-MG was studied in BALB/c and BALB/c nude mice with transplanted tumors. It was found that 7-MG effectively penetrates tumor tissue and suppresses colon adenocarcinoma growth in the Akatol model, as well as in a xenograft model with human HCT116 cells.

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Antitumor effect of the curaxin CBL0137 on the models of colon cancer

Cited by 3 publications

References 14 publications

Prevention of Colorectal Carcinogenesis by DNA-Binding Small-Molecule Curaxin CBL0137 Involves Suppression of Wnt Signaling

Prevention of Colorectal Carcinogenesis by DNA-Binding Small-Molecule Curaxin CBL0137 Involves Suppression of Wnt Signaling

Anti-cancer activity of сuraxin CBL0137 on the models of acute leukemia in vitro

7-Methylguanine Inhibits Colon Cancer Growth <i>in vivo</i>

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