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Leukemia Cell Cycle Chemical Profiling Identifies the G2-Phase Leukemia Specific Inhibitor Leusin-1.

ABSTRACT: Targeting the leukemia proliferation cycle has been a successful approach to developing antileukemic therapies. However, drug screening efforts to identify novel antileukemic agents have been hampered by the lack of a suitable high-throughput screening platform for suspension cells that does not rely on flow-cytometry analyses. We report the development of a novel leukemia cell-based high-throughput chemical screening platform for the discovery of cell cycle phase specific inhibitors that utilizes chemical cell cycle profiling. We have used this approach to analyze the cell cycle response of acute lymphoblastic leukemia CCRF-CEM cells to each of 181420 druglike compounds. This approach yielded cell cycle phase specific inhibitors of leukemia cell proliferation. Further analyses of the top G2-phase and M-phase inhibitors identified the leukemia specific inhibitor 1 (Leusin-1). Leusin-1 arrests cells in G2 phase and triggers an apoptotic cell death. Most importantly, Leusin-1 was more active in acute lymphoblastic leukemia cells than other types of leukemias, non-blood cancers, or normal cells and represents a lead molecule for developing antileukemic drugs.

SUBMITTER: Xia X

PROVIDER: S-EPMC6884739 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Leukemia Cell Cycle Chemical Profiling Identifies the G2-Phase Leukemia Specific Inhibitor Leusin-1.

Xia Xiaoyu X Lo Yu-Chen YC Gholkar Ankur A AA Senese Silvia S Ong Joseph Y JY Velasquez Erick F EF Damoiseaux Robert R Torres Jorge Z JZ

ACS chemical biology 20190508 5

Targeting the leukemia proliferation cycle has been a successful approach to developing antileukemic therapies. However, drug screening efforts to identify novel antileukemic agents have been hampered by the lack of a suitable high-throughput screening platform for suspension cells that does not rely on flow-cytometry analyses. We report the development of a novel leukemia cell-based high-throughput chemical screening platform for the discovery of cell cycle phase specific inhibitors that utiliz ...[more]

PMID: 31046221

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Project description:BackgroundThe disordered cell cycle and dysregulated expression of numerous oncogenes involved in tumor-relevant processes are highly related to the tumorigenesis of cervical cancer. Cyclin-dependent kinase 7 (CDK7) constitutes the indispensable catalytic subunit of CDK-activating kinase (CAK), which is required for both cell cycle transition and transcriptional regulation. However, research regarding the antitumor effects of CDK7 inhibition in cervical cancer remains unclear.PurposeOur study aims to explore the antineoplastic effects of the CDK7 inhibitor THZ1 in cervical cancer cells and to find a potential agent for cervical cancer treatment.MethodsThe CRISPR-Cas9 system was used to knock down CDK7. The Cell Counting Kit-8 (CCK-8) assay was used to detect the cell viability after CDK7 depletion and THZ1 treatment. Western blot was employed to detect protein expression. The expression levels of mRNA were assayed through qRT-PCR. Flow cytometry analysis was used to assay the apoptotic cells and cell cycle distribution. Gene expression microarray analysis was used to identify the differential expression of the genes. Subcutaneous xenograft mouse model was performed to test the antineoplastic effects of THZ1 in vivo.ResultsWe revealed that the genetic depletion of CDK7 using the CRISPR-Cas9 system exhibited great cell growth inhibition in cervical cancer cell lines, consistent with the effects of CDK7 blocking using THZ1. Cervical cancer cells were highly sensitive to THZ1 treatment, and a low concentration of THZ1 could induce substantial cell apoptosis. THZ1 specifically perturbed the phosphorylation of cell cycle regulator CDK1 and decreased the expression of cyclin B1, leading to a cell cycle blockage at the G2/M phase and inducing cell growth inhibition. The gene expression microarray analysis showed that massive oncogene transcripts, especially those associated with tumorigenesis, were preferential suppressed after THZ1 treatment. The qRT-PCR confirmed that several essential oncogenes in tumorigenesis (c-MYC, hTERT, RAD51, and BCL-2) and HPV viral oncogenes (E6 and E7) were preferentially repressed by THZ1. Moreover, THZ1 exhibited substantial antineoplastic effects against cervical cancer in vivo without inducing obvious side effects.ConclusionThese findings indicated that the CDK7 inhibitor THZ1 is a potential option in cervical cancer treatment owing to its ability to inhibit cell cycle progression and transcriptional activity.

Dataset Information

Leukemia Cell Cycle Chemical Profiling Identifies the G2-Phase Leukemia Specific Inhibitor Leusin-1.

Publications

Leukemia Cell Cycle Chemical Profiling Identifies the G2-Phase Leukemia Specific Inhibitor Leusin-1.

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