In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide

Xu, Xiulong; Shen, Jikun; Mall, Julian W.; Myers, Jonathan A.; Huang, Wentao; Blinder, Leonard; Saclarides, Theodore J.; Williams, James W.; Chong, Anita S.

doi:10.1016/s0006-2952(99)00228-2

Cited by 75 publications

(73 citation statements)

References 18 publications

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“…Moreover, the effects of leflunomide on RSV-induced AFC inhibition, increased lung water content, and increased BAL UTP levels are all reversed by uridine, but, with the exception of IFN-␣, its effects on BAL proinflammatory cytokines are not. Thus, the beneficial effect of leflunomide on AFC results from its inhibitory effect on de novo pyrimidine synthesis, whereas its immunosuppressive effect results chiefly from nonspecific inhibition of tyrosine kinases, which is consistent with previous studies (11,41). IFN-␣ cannot be the mediator of impaired AFC, because BAL IFN-␣ is reduced in 6-MP-treated mice, despite persistence of impaired AFC on Day 2 in these animals.…”

Section: Effect Of De Novo Nucleotide Synthesis Inhibition On Afcsupporting

confidence: 90%

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Davis

Lazarowski

Hickman-Davis

et al. 2006

Am J Respir Crit Care Med

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Rationale: Previously, we demonstrated that intranasal infection of BALB/c mice with respiratory syncytial virus (RSV) resulted in an early 40% reduction in alveolar fluid clearance (AFC), an effect mediated via P2Y purinergic receptors. Objectives: To confirm that RSV-induced inhibition of AFC is mediated by uridine triphosphate (UTP), and to demonstrate that inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. Methods: BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice by instillation of 5% bovine serum albumin into the dependent lung. Some mice were pretreated with leflunomide or 6-mercaptopurine. Measurements and Main Results: RSV-mediated inhibition of AFC is associated temporally with a 20-nM increase in UTP and ATP content of bronchoalveolar lavage fluid, hypoxemia, and altered nasal potential difference. RSV-mediated nucleotide release, AFC inhibition, and physiologic sequelae thereof can be prevented by pretreatment of mice with the de novo pyrimidine synthesis inhibitor leflunomide, which is not toxic to the mice, and which does not affect RSV replication in the lungs. In contrast, pretreatment of mice with 6-mercaptopurine, an inhibitor of de novo purine synthesis, has no beneficial effect on AFC or other indicators of disease progression. Finally, RSV-mediated inhibition of AFC is prevented by volumeregulated anion channel inhibitors. Conclusion: Pyrimidine synthesis or release pathways may provide novel therapeutic targets to counter the pathophysiologic sequelae of impaired AFC in RSV disease.Keywords: ion transport; paramyxovirus infections; pneumonia, viral; pulmonary edemaThe dominant ion transport process of the alveolar epithelium is active movement of Na ϩ ions from the airspace lining fluid to the interstitium (1). This creates an osmotic gradient, causing water to follow passively. This process of alveolar fluid clearance (AFC) is crucial to efficient gas exchange. Importantly, patients with acute lung injury with intact AFC have lower morbidity and mortality than those with compromised AFC (2).Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in infants and children worldwide (3), but its pathogenesis remains poorly understood. Previously, we demonstrated that infection of BALB/c mice with RSV results in reduced AFC at early time points after infection, and inferred that RSV-mediated inhibition of AFC 2 d after infection was mediated by uridine triphosphate (UTP), acting on P2Y receptors (P2YRs) on lung epithelial cells (4). The aim of the current study was to confirm the central role of UTP in mediating the inhibitory effects of RSV on AFC, and to demonstrate that pharmacologic inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. Furthermore, we demonstrated that blockag...

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Section: Effect Of De Novo Nucleotide Synthesis Inhibition On Afcsupporting

confidence: 90%

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Davis

Lazarowski

Hickman-Davis

et al. 2006

Am J Respir Crit Care Med

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“…17,19 Although exact mechanisms involved in cytotoxic effect of teriflunomide are not clearly understood, of note, the available above studies may imply the DHODH-independent modulation plays a principal role in teriflunomidemediated anti-tumor activity. [11][12][13]15,17,20 Thus, teriflunomide may also be a potent agent for treatment of breast cancer and even TNBC. However, direct evidence of this hypothesis has not yet to be documented.…”

Section: Introductionmentioning

confidence: 99%

Featured Article: Teriflunomide, an immunomodulatory drug, exerts anticancer activity in triple negative breast cancer cells

Huang

Zhang²,

Zhi

et al. 2014

Exp Biol Med (Maywood)

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Triple-negative breast cancer (TNBC) is defined as a group of primary breast cancers lacking expression of estrogen, progesterone, and human epidermal growth factor receptor-2 (HER-2) receptors, characterized by higher relapse rate and lower survival compared with other subtypes. Due to lack of identified targets and molecular heterogeneity, conventional chemotherapy is the only available option for treatment of TNBC, but non-discordant positive therapeutic efficacy could not be achieved. Here, we demonstrated that these TNBC cells were sensitive to teriflunomide, which was a well-known immunomodulatory drug for treatment of relapsing multiple sclerosis (MS). Potent anti-cancer effects in TNBC in vitro, including proliferation inhibition, cell cycle delay, cell apoptosis, and suppression of cell motility and invasiveness, could be achieved with this agent. Of note, we showed that multiple signals involved in TNBC proliferation, survival, migratory, and invasive potential were under regulation by teriflunomide. Among them, we identified down-regulation of growth factor receptors to abolish growth maintenance, suppression of c-Myc, and cyclin D1 to contribute to its anti-proliferative effect, modulation of components of cell cycle to induce S-phase arrest, degradation of Bcl-xL, and up-regulation of BAX via activation of MAPK pathway to induce apoptosis, and inhibition of epithelial-mesenchymal transition (EMT) process, matrix metalloproteinase-9 (MMP9) expression, and inactivation of Src/FAK to reduce TNBC migration and invasion. The results identified teriflunomide may be of therapeutic benefit for the more aggressive and difficult-to-treat breast cancer subtype, indicating the use of teriflunomide for clinical trials for treatment of TNBC patients.

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“…As a step toward a better understanding of this widespread phenomenon, our laboratory utilized a microarray containing 47K CpG loci for DNA methylation analysis to survey the genome-wide methylation present in a subgroup of non-Hodgkin's lymphomas, the small B-cell lymphomas (SBCLs) 1 and acute lymphoblastic leukemia (ALL). 2 These studies identified several genes and loci in which differential methylation was present among histological classes, thus showing that aberrant methylation is a nonrandom event in these malignancies.…”

Section: Letters To the Editormentioning

confidence: 94%

“…Importantly, doses required to block tyrosine phosphorylation are approximately 10-to 100-fold higher than those needed to block pyrimidine synthesis. 2 However, some reports have pointed to other potential effects of Leflunomide, including downregulation of cytokine production and decreased expression of cytokine receptors.…”

Section: The Immunomodulatory Drug Leflunomide Inhibits Cell Cycle Prmentioning

confidence: 99%

The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells

et al. 2007

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antibodies and immune complexes which accelerate platelet removal. 7 Based upon these preliminary observations, we hypothesize that reducing exposure to platelet transfusions and stored platelet supernatant might yield better clinical outcomes in acute leukemia in adults. This hypothesis will need to be assessed in larger randomized trials. Washed, leukoreduced, ABO identical transfusions represent an inexpensive, technically simple and low-risk treatment strategy worth further investigation in patients with acute leukemia. Supplementary Information accompanies the paper on the Leukemia website

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In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide

Cited by 75 publications

References 18 publications

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Featured Article: Teriflunomide, an immunomodulatory drug, exerts anticancer activity in triple negative breast cancer cells

The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells

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