Anticancer drug bortezomib increases interleukin-8 expression in human monocytes

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Bortezomib (BZ) is a proteasome inhibitor effective against hematological malignancies.
• Patient relapse and resistance limit BZ efficacy, with underlying mechanisms often unclear.
• Previous findings indicated BZ increases interleukin-8 (IL-8) in solid tumors, contrasting with other NFκB-regulated genes.

Purpose of the Study:

• To investigate if Bortezomib (BZ) increases interleukin-8 (IL-8) expression in human monocytes and macrophages.
• To elucidate the molecular mechanisms behind BZ-induced IL-8 expression in these immune cells.

Main Methods:

• Treatment of U937 macrophages and peripheral blood mononuclear cells with BZ.
• Stimulation with lipopolysaccharide (LPS) where applicable.
• Analysis of IL-8, IL-6, IL-1, and tumor necrosis factor-α expression.
• Investigation of the role of p38 mitogen-activated protein kinase (MAPK).

Main Results:

• BZ significantly elevated IL-8 expression in both stimulated and unstimulated monocytes and macrophages.
• BZ inhibited the expression of IL-6, IL-1, and tumor necrosis factor-α.
• p38 MAPK activation was identified as essential for BZ-induced IL-8 production.

Conclusions:

• Increased IL-8 production by monocytes and macrophages may contribute to Bortezomib (BZ) resistance.
• Targeting the p38-mediated IL-8 pathway presents a potential strategy to overcome BZ resistance.
• This finding could lead to improved cancer treatment regimens combining BZ with p38 inhibitors.