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The coffee ingredients caffeic acid and caffeic acid phenylethyl ester protect against irinotecan-induced leukopenia and oxidative stress response.

ABSTRACT: BACKGROUND AND PURPOSE:Irinotecan, used in colorectal cancer therapy, is metabolized by glucuronidation involving different UDP-glucuronosyltransferase (UGT)1A isoforms leading to facilitated elimination from the body. Individuals homozygous for the genetic variants UGT1A1*28 (Gilbert syndrome) and UGT1A7*3 are more susceptible to irinotecan side effects, severe diarrhoea and leukopenia. The aim of this study was to investigate the protective effects and active constituents of coffee during irinotecan therapy using humanized transgenic (htg)UGT1A-WT and htgUGT1A-SNP (carry UGT1A1*28 and UGT1A7*3 polymorphisms) mice. EXPERIMENTAL APPROACH:HtgUGT1A mice were pretreated with coffee or caffeic acid (CA) + caffeic acid phenylethyl ester (CAPE) and injected with irinotecan. The effects of coffee and CA + CAPE were investigated using reporter gene assays, immunoblot, TaqMan-PCR, siRNA analyses and blood counts. KEY RESULTS:Only the combination of the two coffee ingredients, CA and CAPE, mediates protective effects of coffee in a model of irinotecan toxicity by activation of UGT1A genes. Coffee and CA + CAPE significantly increased UGT1A expression and activity along with SN-38 glucuronide excretion in irinotecan-injected htgUGT1A mice, resulting in significant improvement of leukopenia, intestinal oxidative stress and inflammation. CONCLUSION AND IMPLICATIONS:In this study, we identify the compounds responsible for mediating the previously reported coffee-induced activation of UGT1A gene expression. CA and CAPE represent key factors for the protective properties of coffee which are capable of reducing irinotecan toxicity, exerting antioxidant and protective effects. Provided that CA + CAPE do not affect irinotecan efficacy, they might represent a novel strategy for the treatment of irinotecan toxicity.

SUBMITTER: Kalthoff S

PROVIDER: S-EPMC7443465 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The coffee ingredients caffeic acid and caffeic acid phenylethyl ester protect against irinotecan-induced leukopenia and oxidative stress response.

Kalthoff Sandra S Paulusch Stefan S Rupp Alexander A Holdenrieder Stefan S Hartmann Gunther G Strassburg Christian P CP

British journal of pharmacology 20200716 18

<h4>Background and purpose</h4>Irinotecan, used in colorectal cancer therapy, is metabolized by glucuronidation involving different UDP-glucuronosyltransferase (UGT)1A isoforms leading to facilitated elimination from the body. Individuals homozygous for the genetic variants UGT1A1*28 (Gilbert syndrome) and UGT1A7*3 are more susceptible to irinotecan side effects, severe diarrhoea and leukopenia. The aim of this study was to investigate the protective effects and active constituents of coffee dur ...[more]

PMID: 32548889

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Project description:Salicylic acid phenylethyl ester (SAPE) was synthesized by Zn(OTf)2-catalyzed selective esterification of salicylic acid and phenylethyl alcohol and studied for its role as an immunomodulatory and anticancer agent. Low toxicity and favorable physical, Lipinski-type, and solubility properties were elucidated by ADME-tox studies. Molecular docking of SAPE against COX-2 revealed favorable MolDockscore, rerank score, interaction energy, internal pose energy, and hydrogen bonding as compared to ibuprofen and indomethacin. An average RMSD of ~ 0.13 nm for the docked complex with stable dynamic equilibrium condition was noted during the 20 ns MD simulation. A low band gap predicting a strong binding affinity at the enzyme's active site was further predicted by DFT analysis. The ester caused a reduction in the percentage of erythrocyte hemolysis and was shown to be non-cytotoxic against human lymphocytes, CaCo-2, and HepG-2 cells by the MTT assay. Moreover, it's in vitro efficacy in inhibiting COX-2 enzyme under both LPS stimulated intestinal cells and direct sequestration assays was found to be higher than salicylic acid and indomethacin. The anticancer activity of SAPE was tested on the breast cancer cell line MCF-7, and potential efficacy was exhibited in terms of decreased cell viability. Flow cytometry analysis exhibited the arrest of the cell cycle at G1/G0 and S phases, during which induction of autophagic vesicle formation and decrease in mitochondrial membrane potential was observed owing to increased ROS production. Furthermore, at these phases, the onset of apoptosis along with DNA damage was also observed. Pre-treatment with SAPE in colitis-induced Wistar rats displayed low disease activity index and reduction in the extent of intestinal tissue disruption and lipid peroxidation. A marked increase of anti-oxidative enzymes viz., catalase, GGT, and GST, and a decrease of pro-inflammatory cytokines IL-6 and TNF-α in the intestinal tissue extracts of the treated groups was noted. The results of this study have sufficient credence to support that the synthesised ester (SAPE) be considered as an anti-oxidative and anti-inflammatory compound with therapeutic potential for the effective management of cancer.

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The coffee ingredients caffeic acid and caffeic acid phenylethyl ester protect against irinotecan-induced leukopenia and oxidative stress response.

Publications

The coffee ingredients caffeic acid and caffeic acid phenylethyl ester protect against irinotecan-induced leukopenia and oxidative stress response.

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