Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and Autophagy
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 prognosi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/5/1281 |
| _version_ | 1797475500244860928 |
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| author | Souvick Roy Yinghui Zhao Yate-Ching Yuan Ajay Goel |
| author_facet | Souvick Roy Yinghui Zhao Yate-Ching Yuan Ajay Goel |
| author_sort | Souvick Roy |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:45:02Z |
| format | Article |
| id | doaj.art-c0e45f38966a4f408c14dde88e69a2d0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:45:02Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c0e45f38966a4f408c14dde88e69a2d02023-11-23T22:48:38ZengMDPI AGCancers2072-66942022-03-01145128110.3390/cancers14051281Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and AutophagySouvick Roy0Yinghui Zhao1Yate-Ching Yuan2Ajay Goel3Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USADepartment of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USABioinformatics Core Facility, City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USAColorectal 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.https://www.mdpi.com/2072-6694/14/5/1281colorectal cancer5FU-resistancecancer stem-like cellsmetforminICG-001 |
| spellingShingle | Souvick Roy Yinghui Zhao Yate-Ching Yuan Ajay Goel Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and Autophagy Cancers colorectal cancer 5FU-resistance cancer stem-like cells metformin ICG-001 |
| title | Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and Autophagy |
| title_full | Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and Autophagy |
| title_fullStr | Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and Autophagy |
| title_full_unstemmed | Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and Autophagy |
| title_short | Metformin and ICG-001 Act Synergistically to Abrogate Cancer Stem Cells-Mediated Chemoresistance in Colorectal Cancer by Promoting Apoptosis and Autophagy |
| title_sort | metformin and icg 001 act synergistically to abrogate cancer stem cells mediated chemoresistance in colorectal cancer by promoting apoptosis and autophagy |
| topic | colorectal cancer 5FU-resistance cancer stem-like cells metformin ICG-001 |
| url | https://www.mdpi.com/2072-6694/14/5/1281 |
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