Methotrexate induces poly(ADP-ribose) polymerase-dependent, caspase 3-independent apoptosis in subsets of proliferating CD4+ T cells

Nielsen, Claus Henrik; Albertsen, Louise; Bendtzen, Klaus; Baslund, Bo

doi:10.1111/j.1365-2249.2007.03335.x

Cited by 27 publications

(22 citation statements)

References 17 publications

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“…Although PARP represents a main cleavage target of caspases, 44 alternative pathways may activate PARP as reported in T lymphocytes treated with methotrexate, lung cancer cells transduced for MBP-1, and breast cancer cells treated with PI3K/mTOR inhibitor. [45][46][47][48] Here, we show that IL-23 exerted also antiproliferative effects on B-ALL cells that may be ascribed to 2 different mechanisms. First, we demonstrated that IL-23 treatment damped in vivo expression of cyclin D1, another target of miR15a, 49 whose functions are directly associated with cancer progression and invasion.…”

Section: Discussionmentioning

confidence: 65%

Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells

Cocco

Canale

Frasson

et al. 2010

Blood

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Section: Discussionmentioning

confidence: 65%

Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells

Cocco

Canale

Frasson

et al. 2010

Blood

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“…Ciclosporin A and tacrolimus bind to speci fic intra cellular receptors (immunophilins) and act by blocking the activation of the transcription factor nuclear fac tor of activated T cells (NFAT) that controls cytokine gene transcription and apoptosis resistance of lympho cytes 18,19 . Moreover, methotrexate affects survival of immune cells by blocking cell proliferation and indu cing apoptosis 20 . This drug also increases endogenous adeno sine release, alters expression of cellular adhesion mol ecules and suppresses production of proinflammatory cytokines 21 .…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

507

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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“…Other studies showed the pro-apoptotic action of DMARDS (non-biologicals) such as sulfasalazine,57 and hydroxichloroquine 58. Methotrexate, which in many cases is used in conjunction with TNF-α antagonists, and cyclophosphamide also promote cellular apoptosis in activated T CD4 and CD8 cells, but not in resting cells, through CD95 sensitivity 59,60…”

Section: Tnf-α Antagonists and Apoptosismentioning

confidence: 99%

Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

Urbano

Soccol

Azevedo

2014

BTT

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Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α) raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products). This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation.

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Methotrexate induces poly(ADP-ribose) polymerase-dependent, caspase 3-independent apoptosis in subsets of proliferating CD4+ T cells

Abstract: SummaryThe mechanism of action of methotrexate (

Cited by 27 publications

References 17 publications

Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells

Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells

Current and emerging therapeutic targets for IBD

Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

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