In vitro antileukemia activity of ZSTK474 on K562 cells  

出　　处：《中国药理学通报》2015年第B11期234-235,共2页Chinese Pharmacological Bulletin

摘　　要：Aim Chronic myelogenous leukemia （CML） is a hematopoietic stem cell cancer caused by the Bcr-Abl tyrosine kinase which arises from Philadelphia chromosome （Ph） translocation. Imatinib showed potent antitumor efficacy on CML but caused resistance, therefore, other chemotherapeutic drugs for CML are expected. Phosphati-dylinositol 3-kinases （PI3Ks） are lipid kinases that preferentially phosphorylate phosphatidylinositol 4,5-bisphos- phate （PIP2） to generate phosphatidylinositol 3,4,5-trisphosphate （PIP3） which activates the downstream Akt and mammalian target of rapamycin （mTOR） , and therefore play important roles in controlling signal pathways involved in cell proliferation, etc. ZSTK474, a specific PI3K inhibitor, was reported to show potent antitumor efficacy on various solid tumors, while the anti｜eukemia effect was not yet reported. Herein, the effects of ZSTK474 on K562 CML cells as well as the adriamycin-resistant human leukemia cells （K562/ADR） are reported. Methods Cell proliferation inhibition was detected by MTT assay. Cell cycle was analyzed by FACS. The expression of cell cycle related molecules like p27 and p21 was detected by western blot and qRT-PCR. Synergistic effect of ZSTK474 and Imatinib was evaluated by MTT assay and analyzed using Calcusyn. Results MTT assay showed that ZSTK474 could inhibit the proliferation of K562 and K562/ADR cells with ICs0 as 4 69 μmol · L^-1 and 7 57 μmol·L^-1 re- spectively. ZSTK474 induced cell cycle G1 arrest in the above two cell lines dose-dependently after 48 h treatment. Western blot analysis demonstrated ZSTK474 treatment decreased the level of cyclin D1 and increased the expres- sion of p27 and p21. Similar results in mRNA level were obtained by qRT-PCR assay. Combination of ZSTK474 and Imatinib indicated synergistic effect in both cell lines. Conclusion ZSTK474 exhibited anti-leukemia activity alone, and showed synergistic effect when combined with Imatinib, on CML K562 cells. These findings suggest possible application of

关 键 词：ANTI-LEUKEMIA ZSTK474 K562 K562/ADR cells cell cycle ARREST PI3K INHIBITOR 

分 类 号：R[医药卫生]