In Vitro Antileukemia Activity of ZSTK474 on K562 and Multidrug Resistant K562/A02 Cells

Abstract

Chronic myelogenous leukemia (CML) is a malignant hematological disorder mainly caused by the Bcr-Abl tyrosine kinase. While Bcr-Abl inhibitors including Imatinib showed antitumor efficacy on many CML patients, resistance was frequently reported in recent years. Therefore, novel drugs for CML are still expected. ZSTK474 is a specific phosphatidylinositol 3-kinase (PI3K) inhibitor that we identified. In the present study, the efficacy of ZSTK474, alone or in combination with Imatinib, on K562 CML cells as well as on its multidrug resistance counterpart K562/A02 cells, was investigated. ZSTK474 inhibited the cell proliferation with an IC50 of 4.69 μM for K562 and 7.57 μM for K562/A02 cells, respectively. Treatment by ZSTK474 resulted in cell cycle arrest in G1 phase, which might be associated with upregulation of p27, and downregulation of cyclin D1. ZSTK474 also inhibited phosphorylation of Akt and GSK-3β, which might be involved in the effect on the above cell cycle-related proteins. Moreover, combination of ZSTK474 and Imatinib indicated synergistic effect on both cell lines. In conclusion, ZSTK474 exhibited antileukemia activity alone, and showed synergistic effect when combined with Imatinib, on CML K562 cells as well as the multidrug resistant ones, providing a potential therapeutic approach for CML patients.

Expression Profile Screening and Bioinformatics Analysis of Circrna, Lncrna and Mrna in Acute Myeloid Leukemia Drug-Resistance Cells

“…Sui et al [25] reported that activation of the PI3K/Akt/NF-κB pathway promotes P-gp expression, and the inhibition of this pathway reverses P-gp-mediated multidrug resistance. Zhou et al explored the effect of the PI3K-specific inhibitor ZSTK474 on K562/A02 cells and their results showed that ZSTK474 reversed the resistance of K562/A02 cells to ADM and imatinib by downregulating P-gp expression; accordingly, the target of ZSTK474 for CML treatment is PI3K [26]. It can be seen that PI3K activity plays an important role in the regulation of drug resistance in leukemia.…”

Dual effects of the PI3K inhibitor ZSTK474 on multidrug efflux pumps in resistant cancer cells

“…xenograft models (Yaguchi et al, 2006;Zhou et al, 2016), resulting in cell cycle arrest in G1-phase (Kong and Yamori, 2008). Cell cycle arrest is related to modulating the PI3K/Akt signalling pathway.…”

Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

“…3D). The in vivo anti-angiogenic effect was attributed to its dual inhibition mechanism: inhibition of VEGF secretion in cancer cells and direct inhibition of PI3K in endothelial cells 96 . In addition, ZSTK474 inhibited migration and invasion of prostate cancer cell PC3, and blocked the phosphorylation of Girdin and production of MMPs, suggesting the anti-metastatic activity 34 .…”

“…However, acquired resistance after long term treatment of ZSTK474 has been observed, which might be attributed to over-expression of insulin-like growth factor 1 receptor (IGF1R) 95 . In addition, combination with imatinib exhibited synergic antileukemia activity on chronic myeloid leukemia K562 cells as well as adriamycin-resistant K562/A02 cells 96 . ZSTK474 is now under evaluation in phase I/II clinical trials for treatment of solid tumors.…”