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: Weihua Zhou, Jie Xu, Elise Gelston, Xing Wu, Zhengzhi Zou, Bin Wang, Yunxin Zeng, Hua Wang, Anwen Liu, Lingzhi Xu, Quentin Liu
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 25 Pg. 21557-71 (Aug 28 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26188358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
• Aniline Compounds
• BCL2L1 protein, human
• Benzamides
• Cyclin B1
• Indoles
• Oxindoles
• Quinazolines
• RNA, Small Interfering
• Sulfonamides
• bcl-X Protein
• 2-oxindole
• Vinblastine
• CDC2 Protein Kinase
• CDK1 protein, human
• Cyclin-Dependent Kinases
• navitoclax

Topics

• Aniline Compounds (chemistry)
• Apoptosis
• Benzamides (chemistry)
• CDC2 Protein Kinase
• Cell Cycle
• Cell Line, Tumor (drug effects)
• Cell Proliferation
• Cell Survival
• Cyclin B1 (metabolism)
• Cyclin-Dependent Kinases (metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Leukemic
• Humans
• Indoles (chemistry)
• Leukemia, Myeloid, Acute (metabolism)
• Mitosis
• Oxindoles
• Phosphorylation
• Polyploidy
• Quinazolines (chemistry)
• RNA, Small Interfering (metabolism)
• Sulfonamides (chemistry)
• U937 Cells
• Vinblastine (chemistry)
• bcl-X Protein (antagonists & inhibitors, metabolism)