Chemosensitization by 4-hydroxyphenyl retinamide-induced NF-κB inhibition in acute myeloid leukemia cells

Abstract

Purpose: Inherent and/or acquired multi-drug resistance might be the instigator of treatment failure for acute myeloid leukemia (AML). In the current study, we aimed to explored the chemosensitizing effect of 4-HPR on AML therapy.

Methods: Luciferase reporter assays were used to test the effect of 4-HPR on transcriptional signaling pathways. The quantitative real-time polymerase chain reaction and immunoblots were used to confirm the role of 4-HPR in NF-κB inhibition, apoptosis, and drug resistance. MTT and flow cytometry assays were applied to test the drug response and chemosensitizing effect of 4-HPR with AML cell lines and primary AML samples.

Results: 4-HPR suppressed tumor necrosis factor-α- and daunorubin-induced NF-κB activation in AML cell lines. The expression of anti-apoptotic gene, BCL2, was downregulated, while expressions of pro-apoptotic genes, cIAP, XIAP, and BID, were increased after 4-HPR treatment. Immunoblots showed decreased p65-NF-κB, IκBα, and MDR1, but increased cleaved poly (ADP-ribose) polymerase and BIM. A low concentration of 4-HPR chemosensitized AML cells to daunorubin treatment in vitro.

Conclusion: 4-HPR-induced NF-κB inhibition was the main driver of the chemosensitizing effect observed in AML cell lines and primary AML samples. These results highlight that 4-HPR might be a promising chemosensitizing agent in AML therapy.

Keywords: 4-hydroxyphenyl retinamide; Acute myeloid leukemia; Chemosensitizing effect; Nuclear factor-kappa B inhibition.