Wnt/β-Catenin Small-Molecule Inhibitor CWP232228 Preferentially Inhibits the Growth of Breast Cancer Stem-like Cells.

Breast cancer stem cells (BCSC) are resistant to conventional chemotherapy and radiotherapy, which may destroy tumor masses but not all BCSC that can mediate relapses. In the present study, we showed that the level of Wnt/β-catenin signaling in BCSC is relatively higher than in bulk tumor cells, contributing to a relatively higher level of therapeutic resistance. We designed a highly potent small-molecule inhibitor, CWP232228, which antagonizes binding of β-catenin to T-cell factor (TCF) in the nucleus. Notably, although CWP232228 inhibited the growth of both BCSC and bulk tumor cells by inhibiting β-catenin-mediated transcription, BCSC exhibited greater growth inhibition than bulk tumor cells. We also documented evidence of greater insulin-like growth factor-I (IGF-I) expression by BCSC than by bulk tumor cells and that CWP232228 attenuated IGF-I-mediated BCSC functions. These results suggested that the inhibitory effect of CWP232228 on BCSC growth might be achieved through the disruption of IGF-I activity. Taken together, our findings indicate that CWP232228 offers a candidate therapeutic agent for breast cancer that preferentially targets BCSC as well as bulk tumor cells.

Jang GB ，Hong IS ，Kim RJ ，Lee SY ，Park SJ ，Lee ES ，Park JH ，Yun CH ，Chung JU ，Lee KJ ，Lee HY ，Nam JS ... -  《-》

CWP232228 targets liver cancer stem cells through Wnt/β-catenin signaling: a novel therapeutic approach for liver cancer treatment.

Kim JY ，Lee HY ，Park KK ，Choi YK ，Nam JS ，Hong IS ... -  《Oncotarget》

Selective Wnt/β-catenin Small-molecule Inhibitor CWP232228 Impairs Tumor Growth of Colon Cancer.

To explore the possibility of a selective small-molecule β-catenin inhibitor, CWP232228, as a potential therapeutic drug in the treatment of colorectal cancer (CRC). The effect of CWP2228 on HCT116 cells was analysed in vitro via flow cytometry, western immunoblotting, and luciferase reporter assays. NOD-scid IL2Rgammanull mice were employed for an in vivo xenograft study to validate the in vitro studies. CWP232228 treatment decreased the promoter activity and nuclear expression of β-catenin and induced a significant cytotoxic effect in HCT116 cells. CWP232228 treatment induced apoptosis and cell-cycle arrest in the G1 phase of the cell cycle. Furthermore, CWP232228 decreased the expression of aurora kinase A, c-Myc, cyclin D1 and microphthalmia-associated transcription factor. Lastly, CWP232228 also inhibited the growth of xenografted colon cancer cells in mice. Collectively, CWP232228 may be used as a potential therapeutic drug in CRC.

Kim JY ，Park G ，Krishnan M ，Ha E ，Chun KS ... -  《-》

Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in colon cancer.

Cheltsov A ，Nomura N ，Yenugonda VM ，Roper J ，Mukthavaram R ，Jiang P ，Her NG ，Babic I ，Kesari S ，Nurmemmedov E ... -  《-》

A novel ent-kaurane diterpenoid executes antitumor function in colorectal cancer cells by inhibiting Wnt/β-catenin signaling.

Aberrant activation of Wnt signaling pathway is crucial for the onset and progression of human colorectal cancer (CRC). Owing to the persistent dependence on Wnt signaling for growth and survival, inhibition of this pathway is an attractive approach for new therapies. 11α, 12α-epoxyleukamenin E (EPLE) is a novel ent-kaurane diterpenoid that we previously isolated from Salvia cavaleriei, exhibiting antitumor activities in a variety of cancer cells. Herein, we found that whereas sparing normal human colon mucosal epithelial cells, EPLE selectively inhibited the proliferation of CRC cell lines as well as primary tumor cells. Mechanistically, we demonstrated EPLE exerted its function through suppressing Wnt signaling pathway, as evidenced by EPLE-mediated downregulation of Wnt target genes such as c-Myc, Axin2 and Survivin. Consistently, luciferase reporter assays showed that the EPLE directly blocked Wnt/β-catenin-mediated transcriptional activation. In combination of co-immunoprecipitation and protein structure-based analyses, we determined that the EPLE entered the interface of β-catenin/TCF4 complexes and blocked their interaction that is required for β-catenin-mediated transcriptional activation. Moreover, overexpression of β-catenin alleviated the cytotoxicity of EPLE in CRC cells, supporting Wnt signaling is a major and specific target of EPLE. Combined treatments of EPLE and 5-fluorouracil, the first-line chemotherapy for CRC patients, achieved a synergistic effect. More importantly, EPLE hampered tumor development in a CRC xenograft model. Our data thus establish EPLE as a novel inhibitor of Wnt signaling that holds great promise as a potential candidate for further preclinical evaluation for CRC treatments.

Ye Q ，Yao G ，Zhang M ，Guo G ，Hu Y ，Jiang J ，Cheng L ，Shi J ，Li H ，Zhang Y ，Liu H ... -  《-》