Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

Kciuk, Mateusz; Marciniak, Beata; Kontek, Renata

doi:10.3390/ijms21144919

Cited by 157 publications

(91 citation statements)

References 120 publications

(164 reference statements)

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“…This result is in line with the drug resistance profile of S1-IR20 cell line. Furthermore, irinotecan exerted anticancer effects by targeting DNA topo I, therefore alteration of topo I expression may contribute to drug resistance ( 47 ). However, this is unlikely since S1 and S1-IR20 cells showed similar expression levels of topo I.…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line

Yang

Zeng

et al. 2021

Front. Oncol.

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Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an in vitro model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance in vitro and improve CRC treatment in vivo.

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Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line

Yang

Zeng

et al. 2021

Front. Oncol.

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“…Another DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (Tdp1) has attracted considerable interest in the last few years mainly due to its ability to repair DNA lesions caused topoisomerase 1 (Top1) poisons, a well-established class of anticancer drugs [ 4 ]. The anticancer activity of Top1 poisons, camptothecin and its clinically important derivatives, topotecan and irinotecan [ 5 , 6 ], is based on their ability to bind to the covalent intermediate complex Top1/DNA and prevent the restoring of DNA integrity. This leads to the stabilization of the covalent bond between catalytic tyrosine (Y723) of Top1 and the 3′- end of DNA ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

Gladkova

Nechepurenko

Bredikhin

et al. 2020

IJMS

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A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.

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“…The effect of Irinotecan on cancer is modeled by

, because Irinotecan prevents DNA replication by inhibiting the topoisomerase 1 gene (TOP1) causing subsequent cell death [ 101 , 102 , 103 ]. Although used as a part of the FOLFIRI regimen, it is also given individually in the treatment of cancer.…”

Section: Methodsmentioning

confidence: 99%

Data Driven Mathematical Model of FOLFIRI Treatment for Colon Cancer

Budithi

Kirshtein

et al. 2021

Cancers

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Many colon cancer patients show resistance to their treatments. Therefore, it is important to consider unique characteristic of each tumor to find the best treatment options for each patient. In this study, we develop a data driven mathematical model for interaction between the tumor microenvironment and FOLFIRI drug agents in colon cancer. Patients are divided into five distinct clusters based on their estimated immune cell fractions obtained from their primary tumors’ gene expression data. We then analyze the effects of drugs on cancer cells and immune cells in each group, and we observe different responses to the FOLFIRI drugs between patients in different immune groups. For instance, patients in cluster 3 with the highest T-reg/T-helper ratio respond better to the FOLFIRI treatment, while patients in cluster 2 with the lowest T-reg/T-helper ratio resist the treatment. Moreover, we use ROC curve to validate the model using the tumor status of the patients at their follow up, and the model predicts well for the earlier follow up days.

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Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

Cited by 157 publications

References 120 publications

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line

The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

Data Driven Mathematical Model of FOLFIRI Treatment for Colon Cancer

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