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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 Jan 8

PMID 31906201

Citations 13

Authors

Mehreen Ahmed

Nicholas Jinks

Roya Babaei-Jadidi

Hossein Kashfi

Marcos Castellanos-Uribe

Sean T May

Abhik Mukherjee

Abdolrahman S Nateri

Affiliations

Soon will be listed here.

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 E3-ligase, where AM404 sensitivity was mimicked by -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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