Small-molecule inhibitors of the PERK-mediated Unfolded Protein Response signaling pathway in targeted therapy for colorectal cancer
<b> Introduction:</b> The newest data has reported that endoplasmic reticulum (ER) stress and PERK-dependent Unfolded Protein Response (UPR) signaling pathway may constitute a key factor in colorectal cancer (CRC) pathogenesis on the molecular level. Nowadays used anti-cancer treatment strategies are still insufficient, since patients suffer from various side effects that are directly evoked via therapeutic agents characterized by non-specific action in normal and cancer cells. </br></br> <b>Aim:</b> Thereby, the main aim of the presented research was to analyze the effectiveness of the small-molecule PERK inhibitor NCI 12487 in an in vitro cellular model of CRC. </br></br> <b>Materials and methods:</b> The study was performed on colorectal cancer HT-29 and normal human colon epithelial CCD 841 CoN cell lines. The cytotoxicity was measured by XTT assay, evaluation of apoptosis was performed by caspase-3 assay, whereas cell cycle analysis via the propidium iodide (PI) staining. </br></br> <b>Results:</b> Results obtained have demonstrated that the investigated compound is selective only for HT-29 cancer cells, since at 25 μM concentration it significantly decreased HT-29 cells viability in a dose- and time-dependent manner, evoked increased caspase-3 activity and arrest in the G2/M phase of the cell cycle. Moreover, NCI 12487 compound markedly decreased HT-29 cells viability, increased caspase-3 activity and percentage of cells in sub-G0/G1, thus promoted apoptosis of cancer HT-29 cells with induced ER stress conditions. </br></br> <b>Conclusion:</b> Thus, based on the results obtained in this study it may be concluded that small-molecule modulators of the PERK-dependent UPR signaling pathway may constitute an innovative, targeted treatment strategy against CRC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:94 |
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| Enthalten in: |
Polski przeglad chirurgiczny - 94(2022), 6 vom: 15. März, Seite 17-25 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rozpedek-Kaminska, Wioletta [VerfasserIn] |
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| Links: |
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| Themen: |
Apoptosis |
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| Anmerkungen: |
Date Completed 06.12.2022 Date Revised 06.12.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.5604/01.3001.0015.7948 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM349810176 |
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| 520 | |a <b> Introduction:</b> The newest data has reported that endoplasmic reticulum (ER) stress and PERK-dependent Unfolded Protein Response (UPR) signaling pathway may constitute a key factor in colorectal cancer (CRC) pathogenesis on the molecular level. Nowadays used anti-cancer treatment strategies are still insufficient, since patients suffer from various side effects that are directly evoked via therapeutic agents characterized by non-specific action in normal and cancer cells. </br></br> <b>Aim:</b> Thereby, the main aim of the presented research was to analyze the effectiveness of the small-molecule PERK inhibitor NCI 12487 in an in vitro cellular model of CRC. </br></br> <b>Materials and methods:</b> The study was performed on colorectal cancer HT-29 and normal human colon epithelial CCD 841 CoN cell lines. The cytotoxicity was measured by XTT assay, evaluation of apoptosis was performed by caspase-3 assay, whereas cell cycle analysis via the propidium iodide (PI) staining. </br></br> <b>Results:</b> Results obtained have demonstrated that the investigated compound is selective only for HT-29 cancer cells, since at 25 μM concentration it significantly decreased HT-29 cells viability in a dose- and time-dependent manner, evoked increased caspase-3 activity and arrest in the G2/M phase of the cell cycle. Moreover, NCI 12487 compound markedly decreased HT-29 cells viability, increased caspase-3 activity and percentage of cells in sub-G0/G1, thus promoted apoptosis of cancer HT-29 cells with induced ER stress conditions. </br></br> <b>Conclusion:</b> Thus, based on the results obtained in this study it may be concluded that small-molecule modulators of the PERK-dependent UPR signaling pathway may constitute an innovative, targeted treatment strategy against CRC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a PERK inhibitors | |
| 650 | 4 | |a apoptosis | |
| 650 | 4 | |a cancer treatment | |
| 650 | 4 | |a colorectal cancer | |
| 650 | 4 | |a endoplasmic reticulum stress | |
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| 700 | 1 | |a Piotrzkowska, Danuta |e verfasserin |4 aut | |
| 700 | 1 | |a Galita, Grzegorz |e verfasserin |4 aut | |
| 700 | 1 | |a Pytel, Dariusz |e verfasserin |4 aut | |
| 700 | 1 | |a Kucharska, Ewa |e verfasserin |4 aut | |
| 700 | 1 | |a Dziki, Łukasz |e verfasserin |4 aut | |
| 700 | 1 | |a Dziki, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Majsterek, Ireneusz |e verfasserin |4 aut | |
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