Esterified derivatives of DHA and EPA increase bortezomib cytotoxicity in human multiple myeloma cells

Background & aims: Although the proteasome inhibitor bortezomib has greatly improved the clinical outcome of patients with multiple myeloma (MM), acquired drug resistance remains the greatest obstacle on the road of treating MM. We previously showed that omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) with the chemotherapeutic agent bortezomib can overcome its chemoresistance in MM cells. However, most DHA/EPA are esterified shortly after oral administration, which may affect their bioactivity. This study was to evaluate the cytotoxicity of ethyl ester-DHA/EPA in human MM cells. The mechanisms relevant for the cytotoxicity of these esterified-fatty acids were further investigated. Methods: Human MM cell lines L363, OPM2, U266 were treated with ethyl ester-DHA/EPA with or without bortezomib. The percentage of dead cells and intracellular reactive oxygen species (ROS) levels were analyzed by flow cytometry. Results: Ethyl ester-DHA and -EPA were much more potent than DHA/EPA to induce cytotoxicity in MM cells, even in DHA/EPA-resistant MM cells. Pretreating MM cells with esterified-DHA/EPA before bortezomib potently increased its cytotoxicity. Additionally, intracellular ROS levels were upregulated in MM cells after treatment with ethyl ester-DHA/EPA, which reflected the enhanced oxidative stress in treated cells. Conclusions: This study provides evidence that ethyl ester-DHA/EPA in combination with bortezomib may improve the overall efficacy in MM cells, similar to DHA/EPA, relieving the concern that esterification of DHA/ EPA may affect its bioactivity and further supporting the potential clinical use of fatty acids DHA/EPA for combating drug resistance during MM therapy.

Automated summary

This study found that ethyl ester-DHA/EPA can induce stronger cytotoxicity in MM cells, even in resistant cells. Pretreating MM cells with ethyl ester-DHA/EPA can enhance the cytotoxicity of bortezomib. Additionally, treatment with ethyl ester-DHA/EPA resulted in increased intracellular ROS levels, reflecting enhanced oxidative stress in treated cells.