Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer
The second and third most frequently diagnosed cancers worldwide are breast (2.3 million new cases) and colorectal (1.9 million new cases), respectively. Although advances in cancer therapies and early detection have improved the overall survival of patients, patients still develop resistance or can...
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2025-02-01
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| author | Hector Esquer Qiong Zhou Daniel V. LaBarbera |
| author_facet | Hector Esquer Qiong Zhou Daniel V. LaBarbera |
| author_sort | Hector Esquer |
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| description | The second and third most frequently diagnosed cancers worldwide are breast (2.3 million new cases) and colorectal (1.9 million new cases), respectively. Although advances in cancer therapies and early detection have improved the overall survival of patients, patients still develop resistance or cancer recurrence. Thus, the development of novel therapies that can affect multiple mechanisms of drug resistance and cell survival is ideal for the treatment of advanced and metastatic cancers. CHD1L is a novel oncogenic protein involved in regulating chromatin remodeling, DNA damage repair, epithelial-mesenchymal transition (EMT), and programmed cell death via PARthanatos. Herein, we assess in real-time how the CHD1L inhibitor (CHD1Li) OTI-611 modulates cell cycle progression in Colo678, SUM149PT, and SW620 cell lines. By utilizing a cell cycle reporter, we tracked the real-time cell cycle progression of cancer cells treated with OTI-611 alone and in combination with standard-of-care (SOC) therapies. Our results indicate that OTI-611 causes G1 phase cell cycle arrest through a CHD1L-mediated mechanism that regulates Cyclin D1 expression and localization. As a result of this mechanism, OTI-611 can reprogram the cell cycle effects of other antitumor agents to modulate and arrest cells in G1 when used in combination, including agents commonly known to arrest cells in the G2/M phase. Therefore, we conclude that OTI-611-induced G1 arrest represents a critical component of its unique mechanism of action, contributing significantly to its anticancer activity. |
| format | Article |
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| language | English |
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| spelling | doaj-art-df2ea7c38dcf44ab9848f058ead974e22025-08-20T02:04:36ZengMDPI AGCells2073-44092025-02-0114531810.3390/cells14050318Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal CancerHector Esquer0Qiong Zhou1Daniel V. LaBarbera2Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USAThe second and third most frequently diagnosed cancers worldwide are breast (2.3 million new cases) and colorectal (1.9 million new cases), respectively. Although advances in cancer therapies and early detection have improved the overall survival of patients, patients still develop resistance or cancer recurrence. Thus, the development of novel therapies that can affect multiple mechanisms of drug resistance and cell survival is ideal for the treatment of advanced and metastatic cancers. CHD1L is a novel oncogenic protein involved in regulating chromatin remodeling, DNA damage repair, epithelial-mesenchymal transition (EMT), and programmed cell death via PARthanatos. Herein, we assess in real-time how the CHD1L inhibitor (CHD1Li) OTI-611 modulates cell cycle progression in Colo678, SUM149PT, and SW620 cell lines. By utilizing a cell cycle reporter, we tracked the real-time cell cycle progression of cancer cells treated with OTI-611 alone and in combination with standard-of-care (SOC) therapies. Our results indicate that OTI-611 causes G1 phase cell cycle arrest through a CHD1L-mediated mechanism that regulates Cyclin D1 expression and localization. As a result of this mechanism, OTI-611 can reprogram the cell cycle effects of other antitumor agents to modulate and arrest cells in G1 when used in combination, including agents commonly known to arrest cells in the G2/M phase. Therefore, we conclude that OTI-611-induced G1 arrest represents a critical component of its unique mechanism of action, contributing significantly to its anticancer activity.https://www.mdpi.com/2073-4409/14/5/318CHD1LCHD1L inhibitor (CHD1Li)combination therapycell cycleCyclin D1G1 arrest |
| spellingShingle | Hector Esquer Qiong Zhou Daniel V. LaBarbera Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer Cells CHD1L CHD1L inhibitor (CHD1Li) combination therapy cell cycle Cyclin D1 G1 arrest |
| title | Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer |
| title_full | Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer |
| title_fullStr | Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer |
| title_full_unstemmed | Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer |
| title_short | Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer |
| title_sort | targeted inhibition of chd1l by oti 611 reprograms chemotherapy and targeted therapy induced cell cycle arrest and suppresses proliferation to produce synergistic antitumor effects in breast and colorectal cancer |
| topic | CHD1L CHD1L inhibitor (CHD1Li) combination therapy cell cycle Cyclin D1 G1 arrest |
| url | https://www.mdpi.com/2073-4409/14/5/318 |
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