Abstract 870
Background
Aberrant activation of Wnt/β-catenin signaling is commonly found in colorectal cancers (CRCs) and is the prime event involved in the rapid proliferation of tumor cells in patients with advanced CRC. However, the limited effects of current therapeutics are unsatisfying, which highlights the importance of novel interventions in CRC chemo-treatment. We designed a highly potent small-molecule inhibitor CWP232228, which antagonizes binding of β-catenin to T cell factor in the nucleus. Thus, the present study aimed to explore the possibility of a selective small molecule β-catenin inhibitor, CWP232228, as a potential therapeutic drug in the treatment of CRCs.
Methods
We observed that CWP232228 at a concentration of as low as 1.0 μM induced significant cytotoxic effectsand apoptosis in HCT116. Immunoblot analysis showed that CWP232228 treatment increased the release of cytochrome C, which led to the activation of apical (caspase-9) and effector caspases (caspase-7 and -3) resulting in the increased cleavage of PARP.
Results
In addition, we observed that CWP232228 caused cell cycle arrest via attenuating the expressions of cyclin D2, D3, and survivin. Thus, we validated decreased expressions of Wnt/β-catenin targeted cell cycle progression regulators, aurora kinase A, c-Myc, cyclin D1, and microphthalmia-associated transcription factor.
Conclusions
We confirmed that CWP232228 targets β-catenin via decreased promoter activities, nuclear expressions of β-catenin. Lastly, we found CWP232228 also inhibited growth of xenografted colon cancer cells in NOD-scid IL2Rgammanull mice. Collectively, results in the current study showed a possibility for CWP232228 as a potential therapeutic drug in CRCs.
Clinical trial identification
Editorial acknowledgement
This article is based on research supported by JW pharamaeutical.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3907 - Exploration of efficacious alternative regorafenib regimens to manage hand-foot-skin-reaction (HFSR)
Presenter: Axel Grothey
Session: Poster Display session 2
Resources:
Abstract
3958 - Quality of Life (QoL) in Metastatic Colorectal Cancer (mCRC) in the Real World: Final Results of a European Survey
Presenter: Zorana Maravic
Session: Poster Display session 2
Resources:
Abstract
3563 - BISQUIT: A Randomized Phase II Study of the Administration of Prebiotics and Probiotics During Definitive Treatment With Chemotherapy-radiotherapy for Patients With Squamous Cell Carcinoma of the Anal Canal
Presenter: Rachel Riechelmann
Session: Poster Display session 2
Resources:
Abstract
1184 - iSCORE: Immunotherapy Sequencing in COlon and REctal Cancer
Presenter: Fiona Turkes
Session: Poster Display session 2
Resources:
Abstract
3346 - Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA Study
Presenter: Lisa Salvatore
Session: Poster Display session 2
Resources:
Abstract
3895 - A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study.
Presenter: Maria Aurelia Barbera
Session: Poster Display session 2
Resources:
Abstract
2012 - Open Label Phase III Study of Arfolitixorin vs. Leucovorin in mFOLFOX-6 for First Line Treatment of Metastatic Colorectal Cancer: AGENT
Presenter: Josep Tabernero
Session: Poster Display session 2
Resources:
Abstract
2198 - SOLSTICE, a phase 3, randomized, open label study of trifluridine/tipiracil+bevacizumab (bev) versus capecitabine+bev for the 1L treatment of patients with unresectable metastatic colorectal cancer (mCRC) who are not candidates for intensive therapy
Presenter: Thierry Andre
Session: Poster Display session 2
Resources:
Abstract
2921 - A Phase Ib/ II Trial to Assess the Safety and Efficacy of CXD101 in Combination with the PD-1 Inhibitor Nivolumab in Patients with Metastatic, Previously-Treated, Microsatellite-Stable (MSS) Colorectal Carcinoma (short title CAROSELL)
Presenter: Mark Saunders
Session: Poster Display session 2
Resources:
Abstract
3695 - A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation
Presenter: Heinz Josef Lenz
Session: Poster Display session 2
Resources:
Abstract