EPA and DHA have selective toxicity for PBMCs from multiple myeloma patients in a partly caspase-dependent manner

Mortaz, Esmaeil; Moloudizargari, Milad; Khosravi, Adnan; Asghari, Mohammad Hossein; Movassaghi, Masoud; Varahram, Mohammad; Vaezi, Mohammad; Redegeld, Frank A.; Garssen, Johan

doi:10.1016/j.clnu.2019.08.031

Cited by 12 publications

(12 citation statements)

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“…We have shown in our previous studies that EPA and DHA exert apoptotic effects on MM cell lines including L363 [26,27]. Based on these studies, various concentrations of EPA and DHA were tested to find the highest concentration with no apoptotic effects (the highest sub-lethal concentration), which was found to be 12.5 μM.…”

Section: Epa/dha Treatment Of Myeloma Cellsmentioning

confidence: 99%

Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity

et al. 2020

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Background Despite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance. Objectives a) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions. Methods L363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies. Results Myeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)-and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions. Conclusion Our observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment.

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Section: Epa/dha Treatment Of Myeloma Cellsmentioning

confidence: 99%

Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity

et al. 2020

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“…Preclinical studies suggested that DHA and EPA have direct cytotoxic effect in a variety of cancer cells, including multiple human solid tumors, leukemia and lymphomas [7], but showed no cytotoxicity in normal cells [8]. Moreover, these fatty acids showed selective toxicity for PBMCs from multiple myeloma patients, but not for mononuclear cells from healthy donors [9]. These findings further support that the anticancer use of these fatty acids in combination with chemotherapy might be a rational strategy for MM treatment.…”

Section: Introductionmentioning

confidence: 72%

The efficacy of bortezomib in human multiple myeloma cells is enhanced by combination with omega-3 fatty acids DHA and EPA: Timing is essential

2021

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Background & aims: Although bortezomib as one of the first line medicines that has greatly improved the overall survival of patients with multiple myeloma (MM), undesired drug resistance is frequently observed. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been shown to be able to enhance the efficacy of chemotherapeutic drugs in many cancer types. The aim of the present study was to further evaluate the anticancer activity of DHA and EPA in relation to bortezomib chemosensitivity in human MM cells. The potential involvement of NF-kB signaling pathway was studied. Methods: MM cells were treated with DHA/EPA with or without bortezomib. Cell viability was estimated by WST-1 assay. Apoptotic cells were determined through flow cytometry using annexin V and propidium iodide (PI) staining. Protein expression and phosphorylation was investigated by western blotting. Results: Cell type dependent anticancer potential of DHA and EPA was observed in the cell viability assay. DHA and EPA induced apoptosis in L363, OPM2, MM.1S and U266 cell lines through both mitochondrial and death receptor pathways. Treating MM cells with DHA and EPA significantly downregulated IkBa and upregulated phosphorylation of p65, indicating that they triggered NF-kB activation in MM cells. Treating cells with DHA or EPA prior to bortezomib enhanced the induced cell death. However, concomitant use of bortezomib in combination with either of DHA or EPA decreased the cell death induced by bortezomib, indicating that timing of coincubation is important for the effects on chemosensitivity. Conclusions: The present study provides novel evidence for the anticancer effects of DHA and EPA, and highlights their rational utilization in combination with bortezomib to achieve improved therapeutic outcome for MM.

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“…It was reported previously that DHA and EPA can induce apoptosis in MM primary cells [ 15 ] and MM cell lines [ 17 ]. To further investigate the underlying molecular mechanisms, RNA-seq analysis in OPM2 cells was performed and the differentially expressed genes (DEGs) between treated and untreated cells were identified ( p adj < 0.05, |log 2 fold change| > 2) ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…In our previous work, omega-3 polyunsaturated fatty acids (PUFAs), i.e., DHA and EPA, were shown to have selective cytotoxicity against primary MM cells and MM cell lines, but not in normal human PBMCs [ 15 , 16 ]. Moreover, we recently reported EPA and DHA induced apoptosis in human MM cell lines, including L363, OPM2, MM.1S, and U266, through activating intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways.…”

Section: Introductionmentioning

confidence: 99%

Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation

Chen

Zaal

Berkers

et al. 2021

Cells

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Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance.

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EPA and DHA have selective toxicity for PBMCs from multiple myeloma patients in a partly caspase-dependent manner

Cited by 12 publications

References 35 publications

Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity

Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity

The efficacy of bortezomib in human multiple myeloma cells is enhanced by combination with omega-3 fatty acids DHA and EPA: Timing is essential

Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation

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