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Repurposing Antibacterial AM404 as a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells

Ahmed, Mehreen; Jinks, Nicholas; Babaei-Jadidi, Roya; Kashfi, Hossein; Castellanos-Uribe, Marcos; May, Sean T.; Mukherjee, Abhik; Nateri, Abdolrahman S.

Repurposing Antibacterial AM404 as a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells Thumbnail


Authors

Mehreen Ahmed

Nicholas Jinks

Hossein Kashfi

Marcos Castellanos-Uribe



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.

Journal Article Type Article
Acceptance Date Dec 27, 2019
Online Publication Date Dec 31, 2019
Publication Date Dec 31, 2019
Deposit Date Jan 8, 2020
Publicly Available Date Jan 8, 2020
Journal Cancers
Electronic ISSN 2072-6694
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 12
Issue 1
Article Number 106
DOI https://doi.org/10.3390/cancers12010106
Keywords AM404; cancer stem cells; colonosphere; CRC; differentiation; drug screening; FBXL5 E3-ligase; patient derived organoids; resistance and metastasis; tissue explants
Public URL https://nottingham-repository.worktribe.com/output/3690254
Publisher URL https://www.mdpi.com/2072-6694/12/1/106

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