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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Novel therapeutic diiminoquinone exhibits anticancer effects on human colorectal cancer cells in two-dimensional and three-dimensional in vitro models
Alissar Monzer, Kevork Wakimian, Farah Ballout, Samar Al Bitar, Amani Yehya, Mariam Kanso, Nour Saheb, Ayman Tawil, Samer Doughan, Maher Hussein, Deborah Mukherji, Walid Faraj, Hala Gali-Muhtasib, Wassim Abou-Kheir
Alissar Monzer, Farah Ballout, Samar Al Bitar, Department of Biology, American University of Beirut, Beirut 1107-2020, Lebanon
Kevork Wakimian, Amani Yehya, Wassim Abou-Kheir, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
Mariam Kanso, Samer Doughan, Maher Hussein, Walid Faraj, Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
Nour Saheb, Ayman Tawil, Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
Deborah Mukherji, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
Hala Gali-Muhtasib, Department of Biology and Center for Drug Discovery, American University of Beirut, Beirut 1107-2020, Lebanon
Author contributions: Monzer A carried out lab work as part of her PhD thesis, wrote the manuscript, and performed data analysis and interpretation of data (e.g., biostatistics, statistical analysis, and editing); Wakimian K, Ballout F, Al Bitar S, and Yehya A performed initial lab work and participated in data collection; Faraj W, Tawil A, Doughan S, Hussein M, Kanso M, and Saheb N helped in clinical data curation and the consent form for colon cancer patient samples at the American University of Beirut Medical Center; Gali-Muhtasib H and Abou-Kheir W conceived the project, supervised the work, and edited the manuscript draft; All authors have reviewed and approved the final manuscript.
Institutional review board statement: All specimens from the patients were obtained after their informed consent. All experiments involving human subjects were performed in agreement with all ethical considerations of the Institutional Review Board.
Institutional animal care and use committee statement: Prior to any mouse experiment, all mice protocols were reviewed and approved by the Institutional Animal Care and Use Committee (American University of Beirut, Institutional Animal Care and Use Committee).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The ARRIVE Guidelines have been adopted. The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Wassim Abou-Kheir, MSc, PhD, Associate Professor, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Bliss street-Hamra, Beirut 1107-2020, Lebanon. wa12@aub.edu.lb
Received: March 18, 2022
Peer-review started: March 18, 2022
First decision: June 11, 2022
Revised: June 24, 2022
Accepted: August 5, 2022
Article in press: August 5, 2022
Published online: September 7, 2022
Processing time: 165 Days and 12.7 Hours
BACKGROUND
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality. Cancer stem cells (CSCs) in CRC, which are spared by many chemotherapeutics, have tumorigenic capacity and are believed to be the reason behind cancer relapse. So far, there have been no effective drugs to target colon CSCs. Diiminoquinone (DIQ) has shown promising effects on targeting colon cancer. However, there is limited research on the effects of DIQ on eradicating CSCs in CRC.
AIM
To investigate the anticancer potential of DIQ on colon CSCs in two-dimensional (2D) and three-dimensional (3D) models using colonospheres and patient-derived organoids.
METHODS
Various 2D methods have been used to assess the effect and the mechanism of DIQ on HCT116 and HT29 cell lines including cell proliferation and viability assays, migration and invasion assays, immunofluorescence staining, and flow cytometry. The potency of DIQ was also assessed in 3D culture using the sphere formation assay and colon cancer patient-derived organoid model.
RESULTS
Our results showed that DIQ significantly inhibited cell proliferation, migration, and invasion in HCT116 and HT29 cell lines. DIQ treatment induced apoptosis along with an accumulation of HCT116 and HT29 cancer cells in the sub-G1 region and an increase in reactive oxygen species in both CRC cell lines. DIQ reduced sphere-forming and self-renewal ability of colon cancer HCT116 and HT29 stem/progenitor cells at sub-toxic doses of 1 μmol/L. Mechanistically, DIQ targets CSCs by downregulating the main components of stem cell-related -catenin, AKT, and ERK oncogenic signaling pathways. Potently, DIQ displayed a highly significant decrease in both the count and the size of the organoids derived from colon cancer patients as compared to control and 5-fluorouracil conditions.
CONCLUSION
This study is the first documentation of the molecular mechanism of the novel anticancer therapeutic DIQ via targeting CSC, a promising compound that needs further investigation.
Core Tip: Diiminoquinone has anticancer activity against colorectal cancer. Diiminoquinone targets chemoresistant cancer stem cells in three-dimensional in vitro models by downregulating the main components of stem cell-related -catenin, AKT, and ERK oncogenic signaling pathways. Our findings highlight diiminoquinone’s novel therapeutic potential against colorectal cancer.
