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Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway.
Lu, Xiaohua; Yan, Ge; Klauck, Sabine M; Fleischer, Edmond; Klinger, Anette; Sugimoto, Yoshikazu; Shan, Letian; Efferth, Thomas.
Affiliation
  • Lu X; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
  • Yan G; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
  • Klauck SM; Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Fleischer E; MicroCombiChem GmbH, Wiesbaden, Germany.
  • Klinger A; MicroCombiChem GmbH, Wiesbaden, Germany.
  • Sugimoto Y; Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
  • Shan L; The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
  • Efferth T; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
Biochem Pharmacol ; 193: 114788, 2021 11.
Article in En | MEDLINE | ID: mdl-34582772
After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G2M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Eukaryotic Initiation Factor-2 / Cell Survival / Drug Resistance, Neoplasm / EIF-2 Kinase / Activating Transcription Factor 4 / Antineoplastic Agents Limits: Humans Language: En Journal: Biochem Pharmacol Year: 2021 Document type: Article Affiliation country: Germany Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Eukaryotic Initiation Factor-2 / Cell Survival / Drug Resistance, Neoplasm / EIF-2 Kinase / Activating Transcription Factor 4 / Antineoplastic Agents Limits: Humans Language: En Journal: Biochem Pharmacol Year: 2021 Document type: Article Affiliation country: Germany Country of publication: United kingdom