A Novel Small-molecule WNT Inhibitor, IC-2, Has the Potential to Suppress Liver Cancer Stem Cells

Seto, Kenzo; Sakabe, Tomohiko; Itaba, Noriko; Azumi, Junya; Oka, Hiroyuki; Morimoto, Minoru; Umekita, Yoshihisa; Shiota, Goshi

doi:10.21873/anticanres.11727

Cited by 16 publications

(11 citation statements)

References 36 publications

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“…The persistent existence of TCF-β-catenin complex in nuclei is a common feature of cancer [ 20 ]. IC-2, a derivative of ICG-001, is a novel identified small molecular inhibitor targeting Wnt signaling pathway [ 21 ]. Using TOP/FOP flash report gene screening, we showed that, from the small molecular inhibitor library, IC-2 had the most significant inhibitory effect on the Wnt signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

IC-2 Suppresses Proliferation and Induces Apoptosis of Bladder Cancer Cells via the Wnt/β-Catenin Pathway

et al. 2018

Med Sci Monit

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BackgroundThe Wnt/β-catenin signaling pathway participates in many important tumorigeneses processes, including bladder cancer. The inhibition of abnormal activation of Wnt pathways might provide a new approach to tumor treatment. In the present study, we investigated the role of IC-2, a novel Wnt pathways small molecular inhibitor, in bladder cancer tumorigenesis.Material/MethodsBladder cancer cells were treated with various concentrations of IC-2 (0–5 μM) in vitro. The proliferation ability was measured using colony formation assay and apoptosis was measured using flow cytometry analysis. The protein expression was detected using Western blot analysis. Xenograft in vivo assay was performed to assess tumor growth.ResultsIC-2 suppressed the proliferation and aggravated the apoptosis of bladder cancer cells in dose-dependent and time-dependent manners in vitro. Moreover, high concentrations of IC-2 inhibited the Wnt pathway-related protein expression levels, including β-catenin, Cyclin D1, and TCF4. In vivo, administration of IC-2 in xenograft mice decreased the β-catenin expression and reduced the tumor volume.ConclusionsOur results validate the tumor-inhibition effect of IC-2 on bladder cancer in vivo and in vitro, providing a novel therapeutic strategy for bladder cancer.

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Section: Discussionmentioning

confidence: 99%

IC-2 Suppresses Proliferation and Induces Apoptosis of Bladder Cancer Cells via the Wnt/β-Catenin Pathway

et al. 2018

Med Sci Monit

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“…In hepatic cancers, CD44 has been extensively used in combination with other putative surface markers to isolate CSCs from tumors. Interestingly, CD44 + /CD90 + cells [ 122 ] and CD44 + /CD133 + [ 123 ] cells isolated from human HCC present a more aggressive phenotype than either CD133 positive or CD90 positive cells alone. Lee et al revealed that CD44 + subpopulations higher self-renewal and circulating capacities than CD44 − compartment in a graft model [ 124 ].…”

Section: Surface Marker-based Therapiesmentioning

confidence: 99%

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

Lee

Hong

2020

Cancers

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The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.

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“…Currently, CWP232291 is in a phase IIa clinical trial for leukemia (NCT03055286) [61]. IC2, another derivative of CWP232228, has demonstrated effective suppression of liver cancer stem cells and cancer stem cell marker positive population in vitro and in vivo [167]. Future research developing small molecules capable to modulate stem cells and hematopoietic cell lineage, may also eliminate cancer stem cells and serve as promising therapeutic approach.…”

Section: Metastasis Outgrowth-intervention Of Settlementmentioning

confidence: 99%

Small Ones to Fight a Big Problem—Intervention of Cancer Metastasis by Small Molecules

Kobelt

Dahlmann

Dumbani

et al. 2020

Cancers

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Metastasis represents the most lethal attribute of cancer and critically limits successful therapies in many tumor entities. The clinical need is defined by the fact that all cancer patients, who have or who will develop distant metastasis, will experience shorter survival. Thus, the ultimate goal in cancer therapy is the restriction of solid cancer metastasis by novel molecularly targeted small molecule based therapies. Biomarkers identifying cancer patients at high risk for metastasis and simultaneously acting as key drivers for metastasis are extremely desired. Clinical interventions targeting these key molecules will result in high efficiency in metastasis intervention. In result of this, personalized tailored interventions for restriction and prevention of cancer progression and metastasis will improve patient survival. This review defines crucial biological steps of the metastatic cascade, such as cell dissemination, migration and invasion as well as the action of metastasis suppressors. Targeting these biological steps with tailored therapeutic strategies of intervention or even prevention of metastasis using a wide range of small molecules will be discussed.

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A Novel Small-molecule WNT Inhibitor, IC-2, Has the Potential to Suppress Liver Cancer Stem Cells

Abstract: The novel derivative of small-molecule WNT inhibitor, IC-2, has the potential to suppress liver CSCs and can serve as a promising therapeutic agent to improve the prognosis of patients with HCC.

Cited by 16 publications

References 36 publications

IC-2 Suppresses Proliferation and Induces Apoptosis of Bladder Cancer Cells via the Wnt/β-Catenin Pathway

IC-2 Suppresses Proliferation and Induces Apoptosis of Bladder Cancer Cells via the Wnt/β-Catenin Pathway

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

Small Ones to Fight a Big Problem—Intervention of Cancer Metastasis by Small Molecules

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