Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

Pallasch, Christian P.; Schwamb, Janine; Königs, Sonja Katharina; Schulz, Alexandra; Debey, Svenja; Kofler, David M.; Schultze, Joachim L.; Hallek, Michael; Ultsch, Alfred; Cm, Wendtner

doi:10.1038/sj.leu.2405058

Cited by 86 publications

(73 citation statements)

References 42 publications

(45 reference statements)

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“…Together with data from other groups, the present study underscores the importance of lipid metabolism for activated and malignant human B cells (84). Given that inhibitors of geranylgeranylation are still in the early phases of clinical development and that there are numerous statins that are already on the market, lipophilic statins such as simvastatin and atorvastatin appear to be ideal candidates for the rapid translation into clinical application.…”

Section: Discussionsupporting

confidence: 54%

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Shimabukuro‐Vornhagen

Zoghi

Liebig

et al. 2014

The Journal of Immunology

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Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.

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Section: Discussionsupporting

confidence: 54%

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Shimabukuro‐Vornhagen

Zoghi

Liebig

et al. 2014

The Journal of Immunology

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“…Recently, we demonstrated BCR-induced expression of LPL as a prognostic and pathogenetic factor in CLL. 21 An unmutated status of the IgV H gene was shown to exhibit enhanced autoreactivity and was shown to be the most reliable predictor of prognosis in CLL. 22 Interestingly, we could show that IgV H -unmutated CLL cases exhibited significantly higher expression levels of TOSO.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

Pallasch¹,

Schulz²,

Kutsch³

et al. 2008

Blood

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“…Although the doses used here to exert the proapoptotic and antiproliferative actions of BEZ exceed this by 20-fold, experience of overdose in humans and rhesus monkeys indicates that 30 times the standard daily dose is tolerated without ill effect, for up to a year. 36 On a cautionary note, it has been demonstrated that elevated lipoprotein lipase is a poor risk factor in CLL, 37 that the lipoprotein lipase-inhibitor orlistat induces apoptosis of CLL cells in vitro 38 and that BEZ elevated lipoprotein lipase in hypertriglyceridemic patients during BEZ administration. 39 Medroxyprogesterone acetate has been used to treat breast and renal cell cancers.…”

Section: Discussionmentioning

confidence: 99%

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

et al. 2008

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B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in older adults, remains largely incurable and novel treatments are urgently required. We previously reported powerful pro-apoptotic actions of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against Burkitts lymphoma cells. Here, we demonstrate that BEZ and MPA individually, and more potently when combined (BEZ þ MPA), induce apoptosis of unsorted and CD19 þ ve -selected CLL cells and abrogate the pro-proliferative activity of CD40 L . This action was tumor cell specific, as the drugs had little impact on normal donor cells. The antiproliferative actions of BEZ þ MPA were associated with the generation of reactive oxygen species (ROS), and the proapoptotic actions were associated with the generation of both ROS and mitochondrial superoxide (MSO). BEZ increased prostaglandin D 2 (PGD 2 ) synthesis by CLL cells, and treatment with PGD 2 and its antineoplastic derivative 15dD 12,14, PGJ 2 recapitulated BEZ-induced antiproliferative and proapoptotic actions. The PGD 2 receptor antagonist, BW868C, did not block BEZ or PGD 2 activity against CLL cells. The potency of BEZ þ MPA against CLL cells mirrored that of chlorambucil, and BEZ þ MPA combined with chlorambucil was more potent than either treatment alone. Given the known safety profiles of BEZ and MPA, our data warrant further investigation of their potential as novel therapy for CLL.

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Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

Cited by 86 publications

References 42 publications

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

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