Abstract
Simple SummaryColorectal cancer (CRC) is one of the most frequently diagnosed and lethal malignancies. The majority of CRC patients experience disease relapse after the primary curative treatment strategy of surgery followed by 5FU-based chemotherapy. The presence of cancer stem-like cells (CSCs) is considered to be one of the contributing factors to therapy resistance and disease relapse in CRC. Previous studies implicated the role of the Wnt signaling pathway in the maintenance of the CSC phenotype. Therefore, in this study we explored a novel therapeutic strategy using metformin along with ICG-001, a Wnt signaling inhibitor, to abrogate CSC-mediated chemoresistance in CRC. We observed that metformin and ICG-001 abrogate stemness in a synergistic manner by promoting autophagy and apoptosis in 5FU-resistant CRC cells as well as in CRC patient-derived tumor organoids. Hence, metformin and ICG-001 can be used as part of a therapeutic strategy to overcome 5FU-mediated therapeutic resistance in CRC.Colorectal cancer (CRC) remains the third most frequently diagnosed cancer in the United States. The current treatment regimens for CRC include surgery followed by 5FU-based chemotherapy. Cancer stem-like cells (CSCs) have been implicated in 5FU-mediated chemoresistance, which leads to poor prognosis. In this study, we used metformin along with ICG-001, a Wnt signaling inhibitor, to abrogate CSC-mediated chemoresistance in CRC. We observed that 5FU-resistant (5FUR) CRC cells exhibited increased expression of CSC markers and enhanced spheroid formation. Genome-wide transcriptomic profiling analysis revealed that Wnt signaling, colorectal cancer metastasis signaling, etc., were enriched in 5FUR CRC cells. Accordingly, selective targeting of Wnt signaling using ICG-001 along with metformin abrogated CSC-mediated chemoresistance by decreasing the expression of CSC markers and promoting autophagy and apoptosis in a synergistic manner. We also observed that metformin and ICG-001 exhibited anti-tumor activity in CRC patient-derived tumor organoids. In conclusion, our study highlights that metformin and ICG-001 act synergistically and can be used as part of a therapeutic strategy to overcome 5FU-mediated therapeutic resistance in CRC.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide; the American Cancer Society estimated approximately 147,950 new cases of CRC in 2020 in the United States alone [1]
In order to assess the effect of metformin treatment on cell proliferation in CRC cells we performed cell viability assays using a Cell Counting Kit-8 (CCK-8) kit, following metformin treatment in a panel of CRC cells along with two 5FUR paired counterparts
We investigated the molecular mechanisms associated with the anti-proliferative effect of metformin and ICG-001 by investigating programmed cell death mechanisms, such as autophagy and apoptosis
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide; the American Cancer Society estimated approximately 147,950 new cases of CRC in 2020 in the United States alone [1]. CRC are generally treated with the chemotherapeutic drug, 5-fluorouracil (5FU), either given alone or in combination with oxaliplatin and other molecularly targeted drugs [4] While such treatment regimens are effective in improving disease outcomes, their clinical usefulness is often hampered due to the considerable toxicity associated with these treatments, which often cause severe nausea, vomiting, and weight loss, and increase the risk of infectious complications due to immunosuppression [5,6]. Their therapeutic efficacy is limited due to the emergence of chemotherapeutic drug resistance [7,8]. While different chemotherapeutic regimens possess varying therapeutic responses, each regimen is often accompanied with significant adverse effects, therapeutic resistance, and disease relapse, collectively highlighting the need to develop improved therapeutic modalities to treat this malignancy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
