Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients

Herman, Michal; Weinstein, Talia; Korzets, Asher; Chagnac, Avry; Ori, Yaacov; Zevin, D; Malachi, Tsipora; Gafter, Uzi

doi:10.1067/mlc.2001.111469

Cited by 141 publications

(82 citation statements)

References 14 publications

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“…Procarcinogenic side effects were observed when CsA was used as an immunosuppressant in transplantation medicine. Patients treated with CsA develop tumors much more frequently than control probands that had been treated with, for example, rapamycin, and relations to p53 were considered (Jensen et al, 1999;Herman et al, 2001). In contrast, CsA was found to have chemotherapeutic effects on a variety of cancer cells (Larsson et al, 1991;Ross et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis

et al. 2009

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The functional diversity of the tumor suppressor protein p53 is mainly regulated by protein interactions. In this study, we describe a new interaction with the peptidylprolyl cis/trans isomerase cyclophilin 18 (Cyp18). The interaction reduced the sequence-specific DNA binding of p53 in vitro, whereas the inhibition of the interaction increased p53-reporter gene activity in vivo. The active site of the folding helper enzyme Cyp18 was directly involved in binding. The proline-rich region (amino acids 64-91) of p53 was most likely responsible for the observed binding because a synthetic peptide comprising amino acids 68-81 of p53 inhibited this interaction, and a p53 variant containing a proline residue at position 72 (p53 P72 ) interacted with Cyp18 more effectively than the corresponding p53 R72 variant. Impairment of the Cyp18-p53 interaction induced an accumulation of cells in the G2/M phase of the cell cycle, which was more pronounced when p53 P72 was expressed compared with p53 R72 in an otherwise isogenic cellular background. Moreover, p53-dependent apoptosis was elevated in Cyp18 knockout cells, suggesting an antiapoptotic potential of Cyp18-p53 complexes. Functional in vivo data hint to a possible clinical relevance of the p53-Cyp18 interaction observed.

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Section: Discussionmentioning

confidence: 99%

The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis

et al. 2009

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“…Among these drugs, calcineurin inhibitors have been associated with the development of post-transplant malignancies, such as lymphoma and solid organ tumors. PBMCs from renal transplant recipients undergoing CsA therapy have been observed to exhibit a reduced ability to repair radiation-induced DNA damage (40), which may contribute to carcinogenesis. The CsA-induced production of cytokines, such as transforming growth factor-β and/or vascular endothelial growth factor, may additionally promote carcinogenesis (39,41,42).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation

Witkowska

Strzałka‐Mrozik

Owczarek

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Chronic administration of immunosuppressants has been associated with long-term consequences, including a higher risk of neoplasm development. The processes regulating telomere function exert a major influence on human cancer biology. The present study aimed to assess the effect of immunosuppressive therapy on the expression of genes associated with telomere maintenance and protection in patients following renal transplantation. A total of 51 patients that had undergone kidney transplantation and 54 healthy controls were enrolled in the study. The 51 transplant patients received a three-drug immunosuppressive regimen consisting of cyclosporine A, prednisone and mycophenolate mofetil. In stage 1 of the study, the expression profiles of 123 transcripts, which represented 70 genes, were assessed in peripheral mononuclear blood cells using an oligonucleotide microarray technique in 8 transplant recipients and 4 healthy control subjects. Among the analyzed transcripts, the expression levels of 4 differed significantly between the studied groups; however, only the ACD (adrenocortical dysplasia homolog) gene, encoding the telomere-binding protein POT1-interacting protein 1 (TPP1), was sufficiently specific for telomere homeostasis. The expression of ACD was downregulated in transplant recipients (fold change, 2.11; P=0.006). In stage 2 of the study, reverse transcription-quantitative polymerase chain reaction analysis of ACD, DKC1 and hTERT mRNA was conducted for all transplant patients and control subjects. The results confirmed the downregulation of the ACD gene in patients that had received immunosuppressive therapy (P=0.002). The results of the present study indicate that the downregulation of ACD gene transcription, and thus TPP1 protein expression, may enhance the capacity for cell immortalization, despite normal levels of other key telomere maintenance factors, in patients undergoing immunosuppressive therapy. Furthermore, the results indicate that TPP1 has potential for use as an early clinical marker and/or therapeutic target for cancer in patients following organ transplantation.

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“…[32][33][34] While immunosuppression appears to be the principal predisposing factor, others have argued that compounds such as CsA can also inhibit the repair of DNA damage. 33,[35][36][37] A precedent for the role of immunosuppressive agent-induced DNA damage likely impacting on cancer predisposition has recently been described regarding azathioprine. 38,39 Unrepaired DSBs can result in deletions and/or act as a platform for translocations with obvious implications for malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

O’Driscoll

Jeggo

2008

Bone Marrow Transplant

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Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients

Cited by 141 publications

References 14 publications

The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis

The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

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