Immunotoxicologic effects of cyclosporine on tumor progression in models of squamous cell carcinoma and B-cell lymphoma in C3H mice

Rafferty, Patricia; Egenolf, Devon; Brosnan, Kerry; Makropoulos, Dorie; Jordan, Jarrat L.; Meshaw, Kay; Walker, Mindi; Volk, Amy; Bugelski, Peter J.

doi:10.3109/1547691x.2011.614646

Cited by 15 publications

(9 citation statements)

References 67 publications

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“…One example is CsA, a NFAT signal pathway inhibitor and immunosuppressive drug, which is traditionally associated with an increased risk of neoplasia. However, recent studies provide evidence that CsA (at doses up to 50 mg/kg) does not facilitate tumor progression but partially inhibits tumor growth [36], [37], and the suggestion that CsA could be used in anti-tumor therapy has been emerging. In this study, we showed that in GBM cells, CsA effectively inhibits cell invasion, but has no effect on cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

NFAT1 Is Highly Expressed in, and Regulates the Invasion of, Glioblastoma Multiforme Cells

et al. 2013

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Members of the nuclear factor of activated T cells (NFAT) family have been identified as regulators of oncogenic transformation in several human malignancies. A prominent member of this family, NFAT1, is associated with tumor cell survival, apoptosis, migration and invasion. Here, we investigated the role of NFAT1 in glioma cells. In 111 clinical samples, microarray analysis demonstrated that NFAT1 was over-expressed in glioblastoma multiforme (GBM), compared with low-grade gliomas, a result confirmed by RT-PCR in 24 clinical samples and in the U87 and U251 cell lines. Immunohistochemistry and immunofluorescence stain indicated that over-expressed NFAT1 was mainly located in the nucleus, where it acted as a transcription factor. After treatment with the NFAT antagonist cyclosporin A (CsA) and FK506, levels of NFAT1 in the nuclei of U87 GBM cells were dramatically reduced. The invasive potential of U87 cells was reduced by the same treatment, as well as by inhibition of NFAT1 expression using small hairpin RNA. Proliferation of U87 cells was unaffected by CsA, FK506 and NFAT1 shRNA transfection. Clustering analysis and Pearson correlation analysis of microarray data showed that the expression of NFAT1 correlated with the expression of the invasion-related genes cyclooxygenase-2 (COX-2), matrix metalloproteinase-7 (MMP-7) and MMP-9, a result confirmed by in vitro analysis. These findings demonstrate that NFAT1 contributes to the invasive potential but not the proliferation of GBM cells, and suggest that CsA may find application as an adjuvant in combined treatment strategies for GBM.

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Section: Discussionmentioning

confidence: 99%

NFAT1 Is Highly Expressed in, and Regulates the Invasion of, Glioblastoma Multiforme Cells

et al. 2013

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“…There is no conclusive evidence that ciclosporin is directly mutagenic (Bugelski et al , ; IARC ). Although both ciclosporin and tacrolimus have been shown to promote EBV‐infected B‐cell proliferation (Beatty et al , ), a recent study suggested that ciclosporin may suppress the growth of B‐cell lymphoma in mice (Rafferty et al , ). Our findings for ciclosporin must be replicated and further study is needed to examine the independent association between tacrolimus and NHL risk, even though biological evidence of carcinogenicity is scant (Mistrikova et al , ).…”

Section: Discussionmentioning

confidence: 99%

Iatrogenic immunosuppression and risk of non‐Hodgkin lymphoma in solid organ transplantation: A population‐based cohort study in Australia

Laaksonen

Grulich

et al. 2016

Br J Haematol

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Iatrogenic immunosuppression is a strong risk factor for non-Hodgkin lymphoma (NHL) but the dose-related association between individual immunosuppressive agents and NHL risk is unknown. We conducted a population-based cohort study of 4131 adult Australian liver, heart and lung transplant recipients (1984-2006). We ascertained NHL incidence by probabilistic record linkage between transplant registries and the Australian Cancer Database, and abstracted risk factor data at transplantation and at regular intervals thereafter from medical records. We estimated adjusted hazard ratios (HR) for early (<1 year after transplantation; n = 29) and late (≥1 year; n = 61) NHL using the Fine and Gray proportional subdistribution hazards model that accounted for death as a competing risk. After adjustment for immunosuppression, the risk of both early and late NHL did not significantly differ by organ type. In final models, higher mean daily doses of azathioprine were associated with increased risk of both early [HR 2·20, 95% confidence interval (CI): 1·21-4·01] and late NHL (HR 1·78, 95% CI: 1·12-2·84). There was no association between any other maintenance immunosuppressive agent and NHL risk. This study provides evidence that differences in immunosuppression may explain variation in NHL incidence by organ type, and high doses of azathioprine may independently predict NHL risk.

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“…The lymphoma cell lines showed significant more inhibition of cell growth than the LCLs, at all tested CsA levels. CsA suppressed tumor progression of squamous cell carcinoma and murine B cell lymphoma in a mouse model[ 37 ]. In mouse xenograft models for bladder cancer[ 38 ] and breast cancer[ 39 ] CsA treatment prevented tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Based Identification of Proteins with Deregulated Expression in B Cell Lymphomas

Nijland

Rutgers

et al. 2016

PLoS ONE

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Follicular lymphoma and diffuse large B cell lymphomas comprise the main entities of adult B cell malignancies. Although multiple disease driving gene aberrations have been identified by gene expression and genomic studies, only a few studies focused at the protein level. We applied 2 dimensional gel electrophoresis to compare seven GC B cell non Hodgkin lymphoma (NHL) cell lines with a lymphoblastoid cell line (LCL). An average of 130 spots were at least two folds different in intensity between NHL cell lines and the LCL. We selected approximately 38 protein spots per NHL cell line and linked them to 145 unique spots based on the location in the gel. 34 spots that were found altered in at least three NHL cell lines when compared to LCL, were submitted for LC-MS/MS. This resulted in 28 unique proteins, a substantial proportion of these proteins were involved in cell motility and cell metabolism. Loss of expression of B2M, and gain of expression of PRDX1 and PPIA was confirmed in the cell lines and primary lymphoma tissue. Moreover, inhibition of PPIA with cyclosporine A blocked cell growth of the cell lines, the effect size was associated with the PPIA expression levels. In conclusion, we identified multiple differentially expressed proteins by 2-D proteomics, and showed that some of these proteins might play a role in the pathogenesis of NHL.

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Immunotoxicologic effects of cyclosporine on tumor progression in models of squamous cell carcinoma and B-cell lymphoma in C3H mice

Abstract: (2012) Immunotoxicologic effects of cyclosporine on tumor progression in models of squamous cell carcinoma and B-cell lymphoma in C3H mice, Journal of Immunotoxicology, 9:1, 43-55,

Cited by 15 publications

References 67 publications

NFAT1 Is Highly Expressed in, and Regulates the Invasion of, Glioblastoma Multiforme Cells

NFAT1 Is Highly Expressed in, and Regulates the Invasion of, Glioblastoma Multiforme Cells

Iatrogenic immunosuppression and risk of non‐Hodgkin lymphoma in solid organ transplantation: A population‐based cohort study in Australia

Proteomics Based Identification of Proteins with Deregulated Expression in B Cell Lymphomas

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