Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease

Koide, Hiroyoshi; Tsujimoto, Masayuki; Katsube, Yurie; Ochiai, Megumi; Hojo, Ayako; Furukubo, Taku; Yamakawa, Tomoyuki; Shima, Daisuke; Minegaki, Tetsuya; Nishiguchi, Kohshi

doi:10.1007/s00280-018-3583-y

Cited by 3 publications

(1 citation statement)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we have found decreased levels of the active metabolite of irinotecan, SN-38, in plasma as well as liver but not in tumor tissue of fasted mice [10]. Carboxylesterases (Ces) one to three are needed to convert irinotecan in to its active metabolite SN-38 [20]. The relative upregulation of the carboxylesterases in fasted liver tissue in this study would suggest an increased hydrolysis of irinotecan into SN-38 [7, 21].…”

Section: Discussionmentioning

confidence: 99%

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting

et al. 2019

View full text Add to dashboard Cite

Background Irinotecan use is limited due to severe toxicity. Preconditioning by fasting (PBF) protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of PBF still need to be elucidated. Here, we investigated the transcriptional responses of PBF on irinotecan in both tumor and healthy liver tissue. Experimental approach Male BALB/c mice were subcutaneously injected with C26 colon carcinoma cells. Twelve days after tumor inoculation, two groups were fasted for three days and two groups were allowed food ad libitum (AL). Subsequently, both groups received one dose of irinotecan. Twelve hours after administration mice were sacrificed and blood, tumor and liver tissue were harvested. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses. Key results The AL irinotecan group showed worsened organ function and decreased leukocyte numbers. These effects were abated in PBF animals. PBF led to an altered transcriptional response in the liver of irinotecan-treated mice, including decreased cellular injury and increased stress resistance. Hepatic metabolism of irinotecan was also significantly changed due to PBF. The transcriptional response of tumor tissue observed after PBF was hardly affected compared to AL fed animals. Conclusions Transcriptional changes after PBF to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism. These data help to unravel the mechanisms underlying the effects of fasting on irinotecan and help to improve outcome of chemotherapeutic treatment in cancer patients.

show abstract

Section: Discussionmentioning

confidence: 99%

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting

et al. 2019

View full text Add to dashboard Cite

show abstract

Construction and application of a high-content analysis for identifying human carboxylesterase 2 inhibitors in living cell system

et al. 2020

View full text Add to dashboard Cite

Screening of differential gene expression patterns through survival analysis for diagnosis, prognosis and therapies of clear cell renal cell carcinoma

Ajadee,

Mahmud,

Hossain

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer. Although there is increasing evidence linking ccRCC to genetic alterations, the exact molecular mechanism behind this relationship is not yet completely known to the researchers. Though drug therapies are the best choice after the metastasis, unfortunately, the majority of the patients progressively develop resistance against the therapeutic drugs after receiving it for almost 2 years. In this case, multi-targeted different variants of therapeutic drugs are essential for effective treatment against ccRCC. To understand molecular mechanisms of ccRCC development and progression, and explore multi-targeted different variants of therapeutic drugs, it is essential to identify ccRCC-causing key genes (KGs). In order to obtain ccRCC-causing KGs, at first, we detected 133 common differentially expressed genes (cDEGs) between ccRCC and control samples based on nine (9) microarray gene-expression datasets with NCBI accession IDs GSE16441, GSE53757, GSE66270, GSE66272, GSE16449, GSE76351, GSE66271, GSE71963, and GSE36895. Then, we filtered these cDEGs through survival analysis with the independent TCGA and GTEx database and obtained 54 scDEGs having significant prognostic power. Next, we used protein-protein interaction (PPI) network analysis with the reduced set of 54 scDEGs to identify ccRCC-causing top-ranked eight KGs (PLG, ENO2, ALDOB, UMOD, ALDH6A1, SLC12A3, SLC12A1, SERPINA5). The pan-cancer analysis with KGs based on TCGA database showed the significant association with different subtypes of kidney cancers including ccRCC. The gene regulatory network (GRN) analysis revealed some crucial transcriptional and post-transcriptional regulators of KGs. The scDEGs-set enrichment analysis significantly identified some crucial ccRCC-causing molecular functions, biological processes, cellular components, and pathways that are linked to the KGs. The results of DNA methylation study indicated the hypomethylation and hyper-methylation of KGs, which may lead the development of ccRCC. The immune infiltrating cell types (CD8+ T and CD4+ T cell, B cell, neutrophil, dendritic cell and macrophage) analysis with KGs indicated their significant association in ccRCC, where KGs are positively correlated with CD4+ T cells, but negatively correlated with the majority of other immune cells, which is supported by the literature review also. Then we detected 10 repurposable drug molecules (Irinotecan, Imatinib, Telaglenastat, Olaparib, RG-4733, Sorafenib, Sitravatinib, Cabozantinib, Abemaciclib, and Dovitinib.) by molecular docking with KGs-mediated receptor proteins. Their ADME/T analysis and cross-validation with the independent receptors, also supported their potent against ccRCC. Therefore, these outputs might be useful inputs/resources to the wet-lab researchers and clinicians for considering an effective treatment strategy against ccRCC.

show abstract

Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease

Abstract: The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.

Cited by 3 publications

References 32 publications

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting

Construction and application of a high-content analysis for identifying human carboxylesterase 2 inhibitors in living cell system

Screening of differential gene expression patterns through survival analysis for diagnosis, prognosis and therapies of clear cell renal cell carcinoma

Contact Info

Product

Resources

About