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Repurposing Antibacterial AM404 as a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells
Mehreen Ahmed1, Nicholas Jinks1, Roya Babaei-Jadidi1,2
1Cancer Genetics & Stem Cell Group, BioDiscovery Institute, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK.
Abstract:
Tumour-promoting inflammation is involved in colorectal cancer (CRC) development and therapeutic resistance. However, the antibiotics and antibacterial drugs and signalling that regulate the potency of anticancer treatment upon forced differentiation of cancer stem-like cell (CSC) are not fully defined yet. We screened an NIH-clinical collection of the small-molecule compound library of antibacterial/anti-inflammatory agents that identified potential candidate drugs targeting CRC-SC for differentiation. Selected compounds were validated in both in vitro organoids and ex vivo colon explant models for their differentiation induction, impediment on neoplastic cell growth, and to elucidate the mechanism of their anticancer activity. We initially focused on AM404, an anandamide uptake inhibitor. AM404 is a metabolite of acetaminophen with antibacterial activity, which showed high potential in preventing CRC-SC features, such as stemness/de-differentiation, migration and drug-resistance. Furthermore, AM404 suppressed the expression of FBXL5 E3-ligase, where AM404 sensitivity was mimicked by FBXL5-knockout. This study uncovers a new molecular mechanism for AM404-altering FBXL5 oncogene which mediates chemo-resistance and CRC invasion, thereby proposes to repurpose antibacterial AM404 as an anticancer agent.
Insights
This study repurposed the antibacterial drug AM404 to treat colorectal cancer (CRC). AM404 effectively targets cancer stem-like cells (CSCs) by inhibiting the FBXL5 oncogene, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Tumor-promoting inflammation is crucial in colorectal cancer (CRC) development and treatment resistance.
- The role of antibacterial agents in modulating cancer stem-like cell (CSC) differentiation and therapeutic response remains unclear.
Purpose of the Study:
- To identify small-molecule compounds targeting CRC-CSCs for differentiation.
- To investigate the potential of repurposing antibacterial agents as anticancer drugs.
Main Methods:
- Screening of a small-molecule compound library of antibacterial/anti-inflammatory agents.
- Validation of candidate compounds using in vitro organoid and ex vivo colon explant models.
- Mechanism of action studies focusing on AM404 and its effect on FBXL5 expression.
Main Results:
- AM404, an anandamide uptake inhibitor and acetaminophen metabolite, demonstrated significant potential in preventing CRC-CSC stemness, migration, and drug resistance.
- AM404 suppressed the expression of the E3-ligase FBXL5.
- FBXL5-knockout models mimicked AM404 sensitivity, indicating FBXL5's role in chemo-resistance and CRC invasion.
Conclusions:
- AM404 exhibits anticancer properties by targeting CRC-CSCs and altering FBXL5 oncogene expression.
- This study proposes repurposing the antibacterial agent AM404 as a novel therapeutic strategy for colorectal cancer.
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