Journal
CANCERS
Volume 12, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/cancers12010106
Keywords
AM404; cancer stem cells; colonosphere; CRC; differentiation; drug screening; FBXL5 E3-ligase; patient derived organoids; resistance and metastasis; tissue explants
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Funding
- National Centre for the Replacement, Refinement & Reduction of Animals in Research via a NC3Rs training grant [NC/P001793/1]
- University of Nottingham
- BBSRC [BB/I001271/1, BB/J018961/1, BB/P024068/1, BB/E01772X/1, BB/E022758/1, BB/L010100/1] Funding Source: UKRI
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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.
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