Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

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...

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Autores principales:	Joelle C. Boulos, Mohamed E. M. Saeed, Manik Chatterjee, Yagmur Bülbül, Francesco Crudo, Doris Marko, Markus Munder, Sabine M. Klauck, Thomas Efferth
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	acute myeloid leukemia drug repurposing multiple myeloma network pharmacology transcriptomics tyrosine kinase inhibitors Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/0287c6085c9e4590b630f9d66419fce4
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spelling	oai:doaj.org-article:0287c6085c9e4590b630f9d66419fce42021-11-25T18:39:33ZRepurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells10.3390/ph141111261424-8247https://doaj.org/article/0287c6085c9e4590b630f9d66419fce42021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1126https://doaj.org/toc/1424-8247Crizotinib 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.Joelle C. BoulosMohamed E. M. SaeedManik ChatterjeeYagmur BülbülFrancesco CrudoDoris MarkoMarkus MunderSabine M. KlauckThomas EfferthMDPI AGarticleacute myeloid leukemiadrug repurposingmultiple myelomanetwork pharmacologytranscriptomicstyrosine kinase inhibitorsMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1126, p 1126 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acute myeloid leukemia drug repurposing multiple myeloma network pharmacology transcriptomics tyrosine kinase inhibitors Medicine R Pharmacy and materia medica RS1-441
spellingShingle	acute myeloid leukemia drug repurposing multiple myeloma network pharmacology transcriptomics tyrosine kinase inhibitors Medicine R Pharmacy and materia medica RS1-441 Joelle C. Boulos Mohamed E. M. Saeed Manik Chatterjee Yagmur Bülbül Francesco Crudo Doris Marko Markus Munder Sabine M. Klauck Thomas Efferth Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
description	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.
format	article
author	Joelle C. Boulos Mohamed E. M. Saeed Manik Chatterjee Yagmur Bülbül Francesco Crudo Doris Marko Markus Munder Sabine M. Klauck Thomas Efferth
author_facet	Joelle C. Boulos Mohamed E. M. Saeed Manik Chatterjee Yagmur Bülbül Francesco Crudo Doris Marko Markus Munder Sabine M. Klauck Thomas Efferth
author_sort	Joelle C. Boulos
title	Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
title_short	Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
title_full	Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
title_fullStr	Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
title_full_unstemmed	Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
title_sort	repurposing of the alk inhibitor crizotinib for acute leukemia and multiple myeloma cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0287c6085c9e4590b630f9d66419fce4
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Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

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