Tissue-infiltrating plasma cells are an important source of carboxylesterase 2 contributing to the therapeutic efficacy of prodrugs

Kühl, Anja A.; Erben, Ulrike; Cieluch, C; Spieckermann, Simone; Gröne, Jörn; Lohneis, Philipp; Pape, Ulrich Frank; Arsenić, Ruža; Utku, Nalân

doi:10.1016/j.canlet.2016.04.041

Cited by 9 publications

(9 citation statements)

References 28 publications

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“…Because CTOs contain multiple cell types including ISCs as well as further differentiated enterocytes, goblet cells, entero-endocrine cells, and Paneth cells 16 , irinotecan metabolism in these different cell types may be different, which could explain the distribution pattern of the parent drug and its metabolites observed by MALDI-MSI in this study. For example, recent immunohistochemical analyses indicate that the expression of CES-2 increases during differentiation of epithelial cells, with the highest expression observed in the surface epithelium, and diminished expression at the base of the crypt 46 . UGT proteins are found in all epithelial cells lining the colon 47,48 .…”

Section: Resultsmentioning

confidence: 99%

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

Liu

Flinders

Mumenthaler

et al. 2017

J. Am. Soc. Mass Spectrom.

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Patient-derived colorectal tumor organoids (CTOs) closely recapitulate the complex morphological, phenotypic, and genetic features observed in in vivo tumors. Therefore, evaluation of drug distribution and metabolism in this model system can provide valuable information to predict the clinical outcome of a therapeutic response in individual patients. In this report, we applied matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to examine the spatial distribution of the drug irinotecan and its metabolites in CTOs from two patients. Irinotecan is a prodrug and is often prescribed as part of therapeutic regimes for patients with advanced colorectal cancer. Irinotecan shows a time-dependent and concentration-dependent permeability and metabolism in the CTOs. More interestingly, the active metabolite SN-38 does not co-localize well with the parent drug irinotecan and the inactive metabolite SN-38G. The phenotypic effect of irinotecan metabolism was also confirmed by a viability study showing significantly reduced proliferation in the drug treated CTOs. MALDI-MSI can be used to investigate various pharmaceutical compounds in CTOs derived from different patients. By analyzing multiple CTOs from a patient, this method could be used to predict patient-specific drug responses and help to improve personalized dosing regimens. Graphical Abstract ᅟ.

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Section: Resultsmentioning

confidence: 99%

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

Liu

Flinders

Mumenthaler

et al. 2017

J. Am. Soc. Mass Spectrom.

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“…Drug–herb/drug combination has become a common clinical practice in the past decades. As previously reported, hCE2 is involved in the metabolic activation or detoxification of many prodrugs, environmental pollutants, and procarcinogens, such as aspirin, procaine, and CPT‐11, all of which have larger ethanol groups and smaller ester groups (Jewell et al, ; Kuhl et al, ; Yang, Shi, Yang, Song, & Yan, ). Of these drugs, CPT‐11 is a typical prodrug, which is mainly hydrolyzed to the active product SN‐38, a topoisomerase I inhibitor, by hCE2 in both the liver and intestine.…”

Section: Discussionmentioning

confidence: 83%

Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

Cao

et al. 2018

Phytotherapy Research

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Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN), and CPT-11 as substrates of hCE2. The results demonstrate that shikonin significantly inhibits the activity of hCE2 when FD and NCEN are used as substrates, whereas the half inhibition concentration value of shikonin increased by 5-30 times when CPT-11 was used as the substrate. The inhibition types of shikonin against hCE2 activity reflected by 3 substrates were all best fit to noncompetitive manners. In addition, shikonin was found to distinctly suppress endogenous hCE2 activity, characterized with attenuated fluorescence. Furthermore, for drugs metabolized by hCE2 with the similar binding sites with FD or NCEN, the estimated magnitudes of area under the curve variation were approximately 9-357% in the presence of shikonin. Also, the area under the curve of CPT-11 could be increased by 1-14% following administration of shikonin. These findings have clear clinical implications for the combination of shikonin and hCE2-metabolizing prodrugs.

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“…CES2 expression differs in non-neoplastic tissues and varies between different tumor types including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma and breast cancer 12,18,29 . Furthermore, high CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable PDAC patients who underwent neoadjuvant FOLFIRINOX treatment 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemical analyses were performed on 3 μm thick Tissue Microarrays (TMAs). As previously described for the analysis of CES2 immunohistochemistry, sections of archived patient samples were subjected to heat-induced epitope retrieval prior to incubation with a rabbit antibody specific for CES2 (ab111751, Abcam; Cambridge, United Kingdom) 12 . CES2 immunoreactivity was visualized using the EnVision + HRP System (K4011; Dako, Glostrup, Denmark) directed against rabbit primary antibodies with diaminobenzidine (DAB; Dako) as chromogen.…”

Section: Methodsmentioning

confidence: 99%

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Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma

Goeppert

Renner

Singer

et al. 2019

Sci Rep

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Carboxylesterase 2 (CES2) is instrumental for conversion of ester-containing prodrugs in cancer treatment. Novel treatment strategies are exceedingly needed for cholangiocarcinoma (CCA) patients. Here, we assessed CES2 expression by immunohistochemistry in a CCA cohort comprising 171 non-liver fluke associated, intrahepatic (n = 72) and extrahepatic (perihilar: n = 56; distal: n = 43) CCAs. Additionally, 80 samples of high-grade biliary intraepithelial neoplastic tissues and 158 corresponding samples of histological normal, non-neoplastic biliary tract tissues were included. CES2 expression was highest in non-neoplastic biliary tissue and significantly decreased in CCA. Patients showing any CES2 expression in tumor cells had a significantly better overall survival compared to negative cases (p = 0.008). This survival benefit was also maintained after stratification of CES2-positive cases, by comparing low, medium and high CES2 expression levels (p-trend = 0.0006). Evaluation of CCA subtypes showed the survival difference to be restricted to extrahepatic tumors. Correlation of CES2 expression with data of tumor-infiltrating immune cells showed that particularly CD8+ T cells were more frequently detected in CES2-positive CCAs. Furthermore, treatment of CCA cell lines with the prodrug Irinotecan reduced cell viability, increased cytotoxicity and modulated inflammatory gene expression. In conclusion, reduced CES2 expression is associated with poor outcome and low CD8+ T cell infiltration in CCA patients. Further clinical studies could show, whether CES2 expression may serve as a predictive marker in patients treated with prodrugs converted by CES2.

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Tissue-infiltrating plasma cells are an important source of carboxylesterase 2 contributing to the therapeutic efficacy of prodrugs

Cited by 9 publications

References 28 publications

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma

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