Mycophenolic Acid Increases Apoptosis, Lysosomes and Lipid Droplets in Human Lymphoid and Monocytic Cell Lines

Cohn, R G; Mirkovich, Anna; Dunlap, Bonnie; Burton, Pamela M.; Chiu, Shu-hui; Eugui, Elsie M.; Caulfield, John P.

doi:10.1097/00007890-199908150-00014

Cited by 125 publications

(76 citation statements)

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“…2,5,6,8 We have also observed that specific GTP depletion by MPA restrained the mitogenesis of insulinsecreting cells by reducing their progression from G1 phase into S and G2/M phases, resulting in apoptosis mediated by activation of caspases. 7,33 In the present study, we defined the linkage between cell cycle arrest and the induction of apoptosis induced by MPA treatment in insulin-secreting cells.…”

Section: Discussionmentioning

confidence: 87%

“…5 MPA depletes cellular GNs, which causes partial reduction in RNA synthesis and drastic inhibition of DNA synthesis, resulting in growth arrest and induction of apoptosis. 2,[5][6][7][8] This effect can be reversed entirely by provision of guanine or guanosine but not of adenine or adenosine. [7][8][9] It has been reported that inhibition of de novo GN synthesis by MPA and other IMPDH inhibitors slows cell proliferation by affecting the S phase of the cell cycle, 8,10 and suppresses the transition of cells from G0 to S phase in early-to mid-G1.…”

Section: Introductionmentioning

confidence: 99%

“…2,[5][6][7][8] This effect can be reversed entirely by provision of guanine or guanosine but not of adenine or adenosine. [7][8][9] It has been reported that inhibition of de novo GN synthesis by MPA and other IMPDH inhibitors slows cell proliferation by affecting the S phase of the cell cycle, 8,10 and suppresses the transition of cells from G0 to S phase in early-to mid-G1. 9,11,12 Cell cycle is coordinated by three families of molecules: cyclins, cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CKIs).…”

Section: Introductionmentioning

confidence: 99%

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p53-independent induction of p21waf1/cip1 contributes to the activation of caspases in GTP-depletion-induced apoptosis of insulin-secreting cells

Huo

Metz

2003

Cell Death Differ

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We investigated the role of some key regulators of cell cycle in the activation of caspases during apoptosis of insulinsecreting cells after sustained depletion of GTP by a specific inosine 5 0 -monophosphate dehydrogenase inhibitor, mycophenolic acid (MPA). p21Waf1/Cip1 was significantly increased following MPA treatment, an event closely correlated with the time course of caspase activation under the same conditions. MPA-induced p21Waf1/Cip1 was not mediated by p53, since p53 mass was gradually reduced over time of MPA treatment. The increment of p21 Waf1/Cip1 by MPA was further enhanced in the presence of a pan-caspase inhibitor, indicating that the increased p21Waf1/Cip1 may occur prior to caspase activation. This notion of association of p21Waf1/Cip1 accumulation with caspase activation and apoptosis was substantiated by using mimosine, a selective p21Waf1/Cip1 inducer independent of p53. Mimosine, like MPA, also increased p21 Waf1/Cip1 , promoted apoptosis and simultaneously increased the activity of caspases. Furthermore, knocking down of p21 Waf1/Cip1 transfection of siRNA duplex inhibited caspase activation and apoptosis due to GTP depletion. In contrast to p21Waf1/Cip1 , a reduction in p27 Kip1 occurred in MPA-treated cells. These results indicate that p21Waf1/Cip1 may act as an upstream signal to block mitogenesis and activate caspases which in turn contribute to induction of apoptosis.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p53-independent induction of p21waf1/cip1 contributes to the activation of caspases in GTP-depletion-induced apoptosis of insulin-secreting cells

Huo

Metz

2003

Cell Death Differ

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“…Potent MPA-inhibition of the ratelimiting enzyme, inosine monophosphate dehydrogenase (IMPDH) [7], is highly selective toward type II IMPDH isozyme over type I because of its specific role in de-novo synthesis of guanosine monophosphate in activated mononuclear cell proliferation. Selective inhibition of type II IMPDH by MPA prevents proliferation of activated T-and B-lymphocytes and allows the agent to exert a potent immunosuppressant effect, as well as it induces apoptosis of activated T-lymphocytes [8]. Immunosuppression is less toxic than anti-rejection therapy to alleviate acute allograft rejection of transplanted organs.…”

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confidence: 99%

Targeted inhibition of glucuronidation markedly improves drug efficacy in mice—A model

Basu

Kole

Basu

et al. 2007

Biochemical and Biophysical Research Communications

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Finding UDP-glucuronosyltransferases (UGT) require protein kinase C-mediated phosphorylation is important information that allows manipulation of this critical system. UGTs glucuronidate numerous aromatic-like chemicals derived from metabolites, diet, environment and, inadvertently, therapeutics to reduce toxicities. As UGTs are inactivated by downregulating PKCs with reversiblyacting dietary curcumin, we determined the impact of gastro-intestinal glucuronidation on free-drug uptake and efficacy using immunosuppressant, mycophenolic acid (MPA), in mice. Expressed in COS-1 cells, mouse GI-distributed Ugt1a1 glucuronidates curcumin and MPA and undergoes irreversibly and reversibly dephosphorylation by PKC-specific inhibitor calphostin-C and generalkinase inhibitor curcumin, respectively, with parallel effects on activity. Moreover, oral curcuminadministration to mice reversibly inhibited glucuronidation in GI-tissues. Finally, successive oraladministration of curcumin and MPA to antigen-treated mice increased serum free-MPA and immunosuppression up to 9-fold. Results indicate targeted inhibition of GI-glucuronidation in mice markedly improved free-chemical uptake and efficacy using MPA as a model.Whereas the primary role of UDP-glucurononsyltransferases (UGT) is to detoxify numerous structurally diverse lipophilic chemicals, including metabolites, dietary constituents, environmental toxicants, carcinogens and, inadvertently, therapeutic chemicals, there is a limited capacity to manipulate glucuronidation to improve protection or reduce premature ‡ Corresponding authors at: National Institutes of Health, Building 10, Room 8D-42, Bethesda, MD 20892-1830, E-mail addresses, telephone and fax numbers: owensi@mail.nih.gov; 301-496-6091, and 301-480-8042; basun@mail.nih.gov, 301-496-8825, 301-451-4288. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Whereas MPA readily forms ether-linked-(MPAG) or acyl-glucuronides (AcMPAG) [9-11], we studied MPA glucuronidation in vitro with human UGTs and found 4 isozymes are avid metabolizers [12] that reach saturation kinetics between 1.6 and 2.4 mM with Km values between 0.25 and 0.55 mM. These UGT isozymes, encoded at the UGT1 complex locus, were found strategically and differentially expressed in the gastrointestinal (GI) mucosa [1]. In this report, we established under both in-vitro and in-vivo conditions that mouse Ugt1a1 also requires phosphorylation, which can be transiently downregulated by nontoxic kinase inhibitor, curcumin [2,3,13], and irreversibly by calphostin-C, similar to that for human UGTs [2,3]. Moreover, effects of...

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“…MPA inhibits the de novo purine synthesis by arresting the cell cycle at the G0/G1 to the S transition phase (7,8), which results in selective inhibition of cell proliferation of B-and T cells (6). Since MPA does not influence the survival of activated B and T cells, it has a delayed clinical response of approximately two to three months (9).…”

Section: Introductionmentioning

confidence: 99%

Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Thijs¹,

Geest²,

Schaft³

et al. 2016

Journal of Dermatological Treatment

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Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93-80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage. ARTICLE HISTORY

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Mycophenolic Acid Increases Apoptosis, Lysosomes and Lipid Droplets in Human Lymphoid and Monocytic Cell Lines

Abstract: Increased apoptosis and terminal differentiation of both lymphocytes and monocytes may promote the antiproliferative, immunosuppressive, and anti-inflammatory effects of MMF seen clinically in transplantation and rheumatoid arthritis.

Cited by 125 publications

References 32 publications

p53-independent induction of p21waf1/cip1 contributes to the activation of caspases in GTP-depletion-induced apoptosis of insulin-secreting cells

p53-independent induction of p21waf1/cip1 contributes to the activation of caspases in GTP-depletion-induced apoptosis of insulin-secreting cells

Targeted inhibition of glucuronidation markedly improves drug efficacy in mice—A model

Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

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