7S,15R-Dihydroxy-16S,17S-epoxy-docosapentaenoic Acid Overcomes Chemoresistance of 5-Fluorouracil by Suppressing the Infiltration of Tumor-Associated Macrophages and Inhibiting the Activation of Cancer Stem Cells in a Colorectal Cancer Xenograft Model

Abstract

Although the tumor bulk is initially reduced by 5-fluorouracil (5-FU), chemoresistance developed due to prolonged chemotherapy in colorectal cancer (CRC). The enrichment of cancer stem cells (CSCs) and the infiltration of tumor-associated macrophages (TAMs) contribute to chemoresistance and poor outcomes. A docosahexaenoic acid derivative developed by our group, 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), exerts antitumor effects against TAMs infiltration and CSCs enrichment in our previous study. The current study aimed to investigate whether diHEP-DPA was able to overcome chemoresistance to 5-FU in CRCs, together with the potential synergistic mechanisms in a CT26-BALB/c mouse model. Our results suggested that although 5-FU inhibited tumor growth, 5-FU enriched CSCs via the WNT/β-catenin signaling pathway, resulting in chemoresistance in CRCs. However, we revealed that 5-FU promoted the infiltration of TAMs via the NF-kB signaling pathway and improved epithelial–mesenchymal transition (EMT) via the signal transducer and activator of the transcription 3 (STAT3) signaling pathway; these traits were believed to contribute to CSC activation. Furthermore, supplementation with diHEP-DPA could overcome drug resistance by decreasing the CSCs, suppressing the infiltration of TAMs, and inhibiting EMT progression. Additionally, the combinatorial treatment of diHEP-DPA and 5-FU effectively enhanced phagocytosis by blocking the CD47/signal regulatory protein alpha (SIRPα) axis. These findings present that diHEP-DPA is a potential therapeutic supplement to improve drug outcomes and suppress chemoresistance associated with the current 5-FU-based therapies for colorectal cancer.

PRRX1-OLR1 axis supports CAFs-mediated lung cancer progression and immune suppression

“…The significance of our findings is underscored by the growing body of research highlighting the active participation of stromal components in cancer progression. Stromal cells, including fibroblasts, play crucial roles in tumor growth, invasion, and therapy resistance [ 34 ]. CAFs, in particular, have emerged as key regulators of these processes, emphasizing the need for targeted therapies aimed at modulating their functions [ 35 ].…”

The Impact of Cancer Stem Cells in Colorectal Cancer

“…Their research highlighted the synergistic effects of diHEP-DPA and 5-FU in reducing tumor size and weight, offering a hopeful avenue for enhancing CRC treatment efficacy. Mechanistic investiga-tions revealed the ability of diHEP-DPA to mitigate 5-FU-induced activation of CSCs and suppress the infiltration of tumor-associated macrophages (TAMs), further emphasizing the complexity of CRC resistance mechanisms [98].…”

Marine Natural Products as Anticancer Agents 2.0

“…Distinct strategies have been designed to overcome these challenges, including drug synergism. Su and collaborators [13] explored the potential of a novel resolvin, 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), synthesized by cyanobacterial lipoxygenase from docosa-hexaenoic acid (DHA) to overcome the chemoresistance to 5-fluorouracil (5-FU) of colorectal cancer cells (CRCs) using in vitro and in vivo models. The new resolvin suppressed key events related to chemoresistance to 5-FU resulting from prolonged exposure, such as the enrichment of CSCs, the infiltration of tumor-associated macrophages, and the epithelial-mesenchymal transition in colorectal tu-mors.…”