Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Joelle C Boulos
- Mohamed EM Saeed
- Manik Chatterjee
- Yagmur Buelbuel
- Francesco Crudo
- Doris Marko
- Markus Munder
- Sabine M Klauck
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000724431800001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3390/ph14111126
- eISSN
- 1424-8247
- Externe Identifier
- Clarivate Analytics Document Solution ID: XG0DF
- PubMed Identifier: 34832908
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- PHARMACEUTICALS
- Schlüsselwörter
- acute myeloid leukemia
- drug repurposing
- multiple myeloma
- network pharmacology
- transcriptomics
- tyrosine kinase inhibitors
- Artikelnummer
- ARTN 1126
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
- Sub types
- Article
- Ausgabe der Zeitschrift
- 14
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p>Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib’s ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.</jats:p>
- Autoren
- Joelle C Boulos
- Mohamed EM Saeed
- Manik Chatterjee
- Yagmur Bülbül
- Francesco Crudo
- Doris Marko
- Markus Munder
- Sabine M Klauck
- Thomas Efferth
- DOI
- 10.3390/ph14111126
- eISSN
- 1424-8247
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- Pharmaceuticals
- Sprache
- en
- Online publication date
- 2021
- Paginierung
- 1126 - 1126
- Status
- Published online
- Herausgeber
- MDPI AG
- Herausgeber URL
- http://dx.doi.org/10.3390/ph14111126
- Datum der Datenerfassung
- 2021
- Titel
- Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
- Ausgabe der Zeitschrift
- 14
Data source: Crossref
- Abstract
- Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of <i>ALK</i>-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where <i>TOP2A</i> and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G<sub>2</sub>M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib's ability to prevent mitotic exit. However, cells accumulated in the sub-G<sub>0</sub>G<sub>1</sub> fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and <i>Vinca</i> alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
- Autoren
- Joelle C Boulos
- Mohamed EM Saeed
- Manik Chatterjee
- Yagmur Bülbül
- Francesco Crudo
- Doris Marko
- Markus Munder
- Sabine M Klauck
- Thomas Efferth
- DOI
- 10.3390/ph14111126
- eISSN
- 1424-8247
- Externe Identifier
- PubMed Identifier: 34832908
- PubMed Central ID: PMC8617756
- Open access
- true
- ISSN
- 1424-8247
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- Pharmaceuticals (Basel, Switzerland)
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2021
- Open access status
- Open Access
- Paginierung
- 1126
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2021
- Titel
- Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 14
Files
https://www.mdpi.com/1424-8247/14/11/1126/pdf?version=1636104433 https://europepmc.org/articles/PMC8617756?pdf=render
Data source: Europe PubMed Central
- Abstract
- Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib's ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.
- Date of acceptance
- 2021
- Autoren
- Joelle C Boulos
- Mohamed EM Saeed
- Manik Chatterjee
- Yagmur Bülbül
- Francesco Crudo
- Doris Marko
- Markus Munder
- Sabine M Klauck
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/34832908
- DOI
- 10.3390/ph14111126
- Externe Identifier
- PubMed Central ID: PMC8617756
- ISSN
- 1424-8247
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- Pharmaceuticals (Basel)
- Schlüsselwörter
- acute myeloid leukemia
- drug repurposing
- multiple myeloma
- network pharmacology
- transcriptomics
- tyrosine kinase inhibitors
- Sprache
- eng
- Country
- Switzerland
- PII
- ph14111126
- Datum der Veröffentlichung
- 2021
- Status
- Published online
- Titel
- Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 14
Data source: PubMed
- Beziehungen:
-