Screening of an FDA-Approved Drug Library: Menadione Induces Multiple Forms of Programmed Cell Death in Colorectal
Liyuan Cao1,2, Weiwei Song2,3, Jinli Sun2
1Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing new drugs is time-consuming and resource-intensive. As a more efficient approach, drug repurposing offers a promising alternative for discovering new therapies. Methods: In this study, we screened 1068 small molecular compounds from an FDA-approved drug library in CRC cells. Menadione was selected for further study based on its activity profile. Mechanistic analysis included a cell death pathway PCR array, differential gene expression, enrichment, and network analysis. Gene expressions were validated by RT-qPCR. Results: We identified menadione as a potent anti-tumor drug. Menadione induced three programmed cell death (PCD) signaling pathways: necroptosis, apoptosis, and autophagy. Furthermore, we found that the anti-tumor effect induced by menadione in CRC cells was mediated through a key gene: MAPK8. Conclusions: By employing methods of cell biology, molecular biology, and bioinformatics, we conclude that menadione can induce multiple forms of PCD in CRC cells by activating MAPK8, providing a foundation for repurposing the "new use" of the "old drug" menadione in CRC treatment.
Insights
Menadione, an existing drug, effectively combats colorectal cancer (CRC) by triggering multiple cell death pathways. This discovery supports repurposing menadione for novel CRC treatments.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Colorectal cancer (CRC) presents significant global health challenges due to high incidence and mortality.
- Existing treatments for CRC face limitations including chemotherapy toxicity and drug resistance.
- Drug repurposing offers an efficient strategy for identifying novel CRC therapies.
Purpose of the Study:
- To screen FDA-approved drugs for potential colorectal cancer (CRC) treatments.
- To investigate the anti-tumor mechanisms of menadione in CRC cells.
- To explore the potential of menadione repurposing for CRC therapy.
Main Methods:
- Screening of 1068 small molecular compounds from an FDA-approved library against CRC cells.
- Mechanistic analysis involving cell death pathway PCR array, differential gene expression, and network analysis.
- Validation of gene expression changes using quantitative real-time PCR (RT-qPCR).
Main Results:
- Menadione demonstrated potent anti-tumor activity in colorectal cancer (CRC) cells.
- Menadione induced multiple programmed cell death (PCD) pathways: necroptosis, apoptosis, and autophagy.
- The anti-tumor effects of menadione were mediated by the activation of the MAPK8 gene.
Conclusions:
- Menadione effectively induces multiple forms of programmed cell death (PCD) in colorectal cancer (CRC) cells.
- MAPK8 activation is a key mechanism underlying menadione's anti-tumor effects in CRC.
- Menadione is a promising candidate for drug repurposing in colorectal cancer (CRC) treatment.
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