Oncotarget

Research Papers:

Antiproliferative effect of ZSTK474 alone or in combination with chemotherapeutic drugs on HL60 and HL60/ADR cells

Qianxiang Zhou _, Yali Chen, Lei Zhang, Yuxu Zhong, Zhe Zhang, Ran Wang, Meihua Jin, Min Gong, Yuling Qiu and Dexin Kong

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Oncotarget. 2017; 8:39064-39076. https://doi.org/10.18632/oncotarget.16589

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Abstract

Qianxiang Zhou1,2, Yali Chen1,2, Lei Zhang1,2, Yuxu Zhong3, Zhe Zhang1, Ran Wang1, Meihua Jin1, Min Gong1, Yuling Qiu1 and Dexin Kong1,2

1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China

2Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

3State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China

Correspondence to:

Dexin Kong, email: kongdexin@tmu.edu.cn

Yuling Qiu, email: qiuyuling@tmu.edu.cn

Keywords: ZSTK474, HL60/ADR, PI3K, resistance, drug combination

Received: November 22, 2016    Accepted: February 28, 2017    Published: March 28, 2017

ABSTRACT

While chemotherapy remains to be one of the main approaches in the clinical treatment of acute myeloid leukemia (AML), multidrug resistance (MDR) has become a serious problem which limits the therapeutic efficacy. The important roles of the PI3K/Akt pathway in modulating cell proliferation and MDR suggest that PI3K inhibitor might be effective for treatment of AML. In the present study, the antiproliferative effects of PI3K inhibitor ZSTK474 on AML cell HL60 and the adriamycin (ADR)-resistant HL60/ADR cells were investigated. Our data indicated that ZSTK474 exhibited potent antiproliferative activity, induced G1 cell cycle arrest, but no obvious apoptosis in both cell lines. Moreover, ZSTK474 affected the protein levels of cell-cycle-related molecules including increased p27, decreased cyclin D1 and phosphorylated Rb in dose-dependent manner. The proteins downstream of PI3K including phosphorylated PDK1, Akt and GSK-3β were reduced in a dose-dependent manner after ZSTK474 treatment. ZSTK474 reversed ADR resistance, increased the intracellular accumulation of ADR, and reduced the expression and function of multidrug resistance (MDR) proteins including both P-gp and MRP1 in HL60/ADR cells. The combination of ZSTK474 and chemotherapeutic drugs cytarabine or vincristine led to a synergistic effect in HL60 and HL60/ADR cells. In conclusion, ZSTK474 showed potent antiproliferative effect on HL60 and HL60/ADR cells; combination with cytarabine or vincristine resulted in synergistic effect. Our results suggest ZSTK474 has the potential to be applied in the treatment of AML patients, while further evidences particularly those about in vivo efficacy are needed.


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