title: Inhibition of Bcl-xL overcomes polyploidy resistance and leads to apoptotic cell death in acute myeloid leukemia cells.
abstract: Small molecular inhibitors or drugs targeting specific molecular alterations are widely used in clinic cancer therapy. Despite the success of targeted therapy, the development of drug resistance remains a challenging problem. Identifying drug resistance mechanisms for targeted therapy is an area of intense investigation, and recent evidence indicates that cellular polyploidy may be involved. Here, we demonstrate that the cell cycle kinase inhibitor, Oxindole-1 (Ox-1), induces mitotic slippage, causing resistant polyploidy in acute myeloid leukemia (AML) cells. Indeed, Ox-1 decreases the kinase activity of CDK1 (CDC2)/cyclin B1, leading to inhibition of Bcl-xL phosphorylation and subsequent resistance to apoptosis. Addition of ABT-263, a Bcl-2 family inhibitor, to Ox-1, or the other polyploidy-inducer, ZM447439 (ZM), produces a synergistic loss of cell viability with greater sustained tumor growth inhibition in AML cell lines and primary AML blasts. Furthermore, genetic knockdown of Bcl-xL, but not Bcl-2, exhibited synergistic inhibition of cell growth in combination with Ox-1 or ZM. These data demonstrate that Bcl-xL is a key factor in polyploidization resistance in AML, and that suppression of Bcl-xL by ABT-263, or siRNAs, may hold therapeutic utility in drug-resistant polyploid AML cells.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.|Department of Oncology, the Second Affiliated Hospital, Nanchang University, Nanchang, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.|Department of Oncology, the Second Affiliated Hospital, Nanchang University, Nanchang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: University of Michigan Medical School, Ann Arbor, Michigan, United States.
authors.forename: Elise
authors.initials: E
authors.lastname: Gelston
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
authors.forename: Zhengzhi
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Ultrasound, Union Hospital, Tongji Medical Collage of Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Hematology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Hematological Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Nanchang University, Nanchang, China.
authors.forename: Anwen
authors.initials: A
authors.lastname: Liu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D017209:Apoptosis; D001549:Benzamides / Q000737:chemistry; D016203:CDC2 Protein Kinase; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D056744:Cyclin B1 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007211:Indoles / Q000737:chemistry; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008938:Mitosis; D000078183:Oxindoles; D010766:Phosphorylation; D011123:Polyploidy; D011799:Quinazolines / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry; D020298:U937 Cells; D014747:Vinblastine / Q000737:chemistry; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D000814:Aniline Compounds; C494811:BCL2L1 protein, human; D001549:Benzamides; D056744:Cyclin B1; D007211:Indoles; D000078183:Oxindoles; D011799:Quinazolines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051020:bcl-X Protein; C022960:2-oxindole; D014747:Vinblastine; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C528561:navitoclax
keywords: Bcl-xL; mitotic slippage; polyploidy; resistance; targeted therapy