| Abstract: |
In the last decade, zebrafish have accompanied the mouse as a robust animal model for cancer research. The possibility of screening small-molecule inhibitors in a large number of zebrafish embryos makes this model particularly valuable. However, the dynamic visualization of fluorescently labeled tumor cells needs to be complemented by a more sensitive, easy, and rapid mode for evaluating tumor growth in vivo to enable high-throughput screening of clinically relevant drugs. In this study we proposed and validated a pre-clinical screening model for drug discovery by utilizing bioluminescence as our readout for the determination of transplanted cancer cell growth and inhibition in zebrafish embryos. For this purpose, we used NanoLuc luciferase, which ensured rapid cancer cell growth quantification in vivo with high sensitivity and low background when compared to conventional fluorescence measurements. This allowed us large-scale evaluation of in vivo drug responses of 180 kinase inhibitors in zebrafish. Our bioluminescent screening platform could facilitate identification of new small-molecules for targeted cancer therapy as well as for drug repurposing. Copyright © 2022 Hason, Jovicic, Vonkova, Bojic, Simon-Vermot, White and Bartunek. |
| Keywords: |
controlled study; unclassified drug; human cell; cancer growth; nonhuman; drug targeting; cell proliferation; animal cell; animal tissue; cell survival; cell cycle; imatinib; melanoma; protein kinase inhibitor; embryo; luciferase; animal experiment; animal model; in vivo study; antineoplastic activity; drug potency; in vitro study; tumor xenograft; drug screening; inhibitor; chronic myeloid leukemia; cancer inhibition; drug research; quantitative analysis; pazopanib; cell migration; intermethod comparison; 4 [4 (1,3 benzodioxol 5 yl) 5 (2 pyridinyl) 1h imidazol 2 yl]benzamide; roscovitine; bioluminescence; zebra fish; zebrafish; fluorescence imaging; cancer transplantation; high-throughput screening; bosutinib; barasertib; 12 (2 cyanoethyl) 6,7,12,13 tetrahydro 13 methyl 5 oxoindolo[2,3 a]pyrrolo[3,4 c]carbazole; alpha [amino(4 aminophenylthio)methylene] 2 (trifluoromethyl)phenylacetonitrile; xenotransplantation; dabrafenib; n [4 [6 methoxy 7 (3 morpholinopropoxy) 4 quinazolinylamino]phenyl]benzamide; doramapimod; ruxolitinib; 4 (4 fluorophenyl) 2 (4 hydroxyphenyl) 5 (4 pyridyl)imidazole; pictilisib; 5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide; n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 difluorophenyl]propanesulfonamide; linsitinib; cancer; human; article; ipatasertib; luciferase assay; ic50; abemaciclib; ribociclib; cobimetinib; hek293-ft cell line; ulixertinib; gedatolisib; k-562 cell line; 1 (3 hydroxybenzyl) 3 [4 (4 pyridinyl) 2 thiazolyl]urea; 3 methyl n [1,4,5,6 tetrahydro 6,6 dimethyl 5 [(1 methyl 4 piperidinyl)carbonyl]pyrrolo[3,4 c]pyrazol 3 yl]butanamide; adezmapimod; amg 900; bay 826; bix 02188; cp 724714; ddr in 1; g 749; gnf 5; gsk 579289a; ly 3009120; mk 5108; ng 25; pp 121; tak 715; thz 1; torin 2; torkinib; proapoptotic activity
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