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Rapid identification of antimicrometastases drugs using integrated model systems with two dimensional monolayer, three dimensional spheroids, and zebrafish xenotransplantation tumors
Afu Fu1; Yu Ming Peh1; Weida Ngan1; Na Wei1; Kathy Qian Luo2
2018
Source PublicationBiotechnology & Applied Microbiology
ISSN1097-0290
Volume115Issue:11Pages:2828-2843
Abstract

Treating systemic metastases at the micrometastatic stage is a potential strategy to inhibit cancer metastasis. This study aims to establish an apoptosis sensor‐based platform for rapid, effective, and noninvasive identification of drugs that can inhibit the proliferation of micrometastatic cancer cells. We stably transfected the plasmid DNA encoding the fluorescence resonance energy transfer‐based caspase‐3 sensor into highly metastatic melanoma B16F10 cells. The resulting B16F10‐C3 cells were applied for screening of antiproliferative and proapoptotic drugs in two‐dimensional (2D) monolayer, three‐dimensional (3D) spheroids, and zebrafish xenotransplantation tumors. All studies were conducted in 96‐well plates in a high throughput manner. Fourteen compounds including six chemotherapeutic drugs and eight kinase inhibitors were tested. Thirteen compounds failed the tests due to: Drug resistance, low efficacy, poor pharmacokinetic profile, and/or high side effects to zebrafish. The only compound that passed all tests was pan‐phosphatidylinositol 3‐kinase (PI3K) inhibitor LY294002, which inhibited the proliferation of B16F10‐C3 cells in both 2D and 3D cultures. More important, it significantly reduced the xenograft tumor size in zebrafish by decreasing the viability of metastatic cancer cells. Our study suggests that the PI3K/AKT pathway is a potential therapeutic target for the reactivation of tumor dormancy and proliferation of micrometastases. Moreover, this integrated approach is effective for rapid identification of systemic antimetastases drugs.

KeywordAntimetastasis Drug Discovery Fluorescence Resonance Energy Transfer Pi3k/akt Pathway Three Dimensional Tumor Spheroids
DOIhttp://dx.doi.org/10.1002/bit.26816
Indexed BySCI
Language英语
WOS Research AreaBiotechnology & Applied Microbiology
WOS SubjectBiotechnology & Applied Microbiology
WOS IDWOS:000448262800014
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Cited Times [WOS]:2   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.School of Chemical and Biomedical Engineering, Nanyang Technological University, , Singapore, Singapore
2.Faculty of Health Sciences, University of Macau, Taipa, , Macau, China
Recommended Citation
GB/T 7714
Afu Fu,Yu Ming Peh,Weida Ngan,et al. Rapid identification of antimicrometastases drugs using integrated model systems with two dimensional monolayer, three dimensional spheroids, and zebrafish xenotransplantation tumors[J]. Biotechnology & Applied Microbiology,2018,115(11):2828-2843.
APA Afu Fu,Yu Ming Peh,Weida Ngan,Na Wei,&Kathy Qian Luo.(2018).Rapid identification of antimicrometastases drugs using integrated model systems with two dimensional monolayer, three dimensional spheroids, and zebrafish xenotransplantation tumors.Biotechnology & Applied Microbiology,115(11),2828-2843.
MLA Afu Fu,et al."Rapid identification of antimicrometastases drugs using integrated model systems with two dimensional monolayer, three dimensional spheroids, and zebrafish xenotransplantation tumors".Biotechnology & Applied Microbiology 115.11(2018):2828-2843.
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