Simvastatin induces apoptosis of B-CLL cells by activation of mitochondrial caspase 9

Chapman-Shimshoni, Daphne; Yuklea, Mona; Radnay, Judith; Shapiro, Hava; Lishner, Michael

doi:10.1016/s0301-472x(03)00192-9

Cited by 74 publications

(60 citation statements)

References 25 publications

(35 reference statements)

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“…Simvastatin reduces cellularity of peripheral lymphoid organs in mice by inhibiting lymphocyte homing Statins have been reported to enhance apoptosis of both human and murine lymphocytes in vitro [5,[20][21][22]; however, little is known about the pro-apoptotic activities of statins in vivo and [23,24], has no adverse effects on liver function [24,25]. At autopsy, spleen and lymph nodes from simvastatin-treated mice were found to be significantly reduced in size compared with carrier-treated mice, which was associated with reduced cellularity.…”

Section: Resultsmentioning

confidence: 99%

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

et al. 2008

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Statins block the activity of HMG-CoA reductase, which catalyses the production of mevalonate, an intermediate in cholesterol biosynthesis, which is also a precursor of isoprenoids. In addition to lowering circulating cholesterol, these drugs display antiinflammatory and immunomodulatory activities in vitro; however, their effects on the development of adaptive immune responses in vivo, as well as the underlying mechanisms, are as yet largely unknown. Here we investigated the outcome of simvastatin treatment on a number of processes, which together orchestrate adaptive immunity to specific antigen. Simvastatin treatment resulted in a marked reduction of T and B cells in spleen, lymph nodes and peripheral blood in mice. This effect could be ascribed principally to an impairment of lymphocyte homing to secondary lymphoid organs. In addition, simvastatin was found to strongly inhibit T-cell responses to the MHCI restricted hen ovalbumin peptide antigen SIINFEKL and to impair ovalbumin uptake and cross-presentation by MHCI. Simvastatin also suppressed antibody responses to immunization with ovalbumin and delayed-type hypersensitivity to allergens. These activities could be largely accounted for by the simvastatin-dependent inhibition of HMG-CoA reductase. The data provide novel mechanistic insight into the activities of simvastatin in the highly complex context of the immune response.Key words: Apoptosis . Homing . Immune responses . Simvastatin IntroductionStatins are competitive inhibitors of HMG-CoA reductase, a major rate-limiting enzyme that controls HMG-CoA conversion to mevalonic acid in the cholesterol biosynthetic pathway. In addition to lowering circulating cholesterol, statins act as antiinflammatory and immunomodulatory agents [1]. These activities have been largely ascribed to their capacity to block isoprenoid production, and thereby to inhibit prenylation of small Ras superfamily GTPases, which are master regulators of cell activation and proliferation, cytoskeletal remodelling and membrane trafficking [2].Statins suppress T-cell activation both directly and by interfering with APC maturation and function. Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also 2832affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppressio...

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Section: Resultsmentioning

confidence: 99%

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

et al. 2008

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“…36,37 It is intriguing that we identified an association with APOE, as the expressed protein has cytostatic and cytotoxic activity; moreover, apolipoprotein levels and activity of aplolipoprotein receptors have been linked to prognosis in B-CLL. [38][39][40] The prior probability of identifying a significant association with prognosis for a series of SNPs mapping to a single DNA repair pathway is intuitively small, thereby providing a measure of robustness to our observations. However, ultimately, replication in independent studies is required to either validate or refute study findings.…”

Section: Org Frommentioning

confidence: 98%

Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis

Sellick

Wade

Richards

et al. 2008

Blood

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To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P ‫؍‬ .03), IL19 S213F (P ‫؍‬ .001), LILRA4 P27L (P ‫؍‬ .004), KLRC4 S29I (P ‫؍‬ .007), and CD5 V471A (P ‫؍‬ .002); and DNA response genes POLB P242R (P ‫؍‬ .04) and TOPBP1 S730L (P ‫؍‬ .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (

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“…3,4 The intake of statins and aspirin was associated with reduced incidence of CLL. 5,6 However, statin intake did not affect treatment-free survival in patients with early CLL.…”

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confidence: 99%

Statin and aspirin use is associated with improved outcome of FCR therapy in relapsed/refractory chronic lymphocytic leukemia

Chae

Trinh

Jain

et al. 2014

Blood

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Simvastatin induces apoptosis of B-CLL cells by activation of mitochondrial caspase 9

Cited by 74 publications

References 25 publications

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis

Statin and aspirin use is associated with improved outcome of FCR therapy in relapsed/refractory chronic lymphocytic leukemia

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