Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E
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Cryptotanshinone (CPT), a diterpene quinone isolated from Salvia miltiorrhiza, is recently reported to have obvious anticancer activities against diverse cancer cells. However, the effect and regulatory mechanism of CPT remain unclear in human chronic myeloid leukemia (CML) cells. In this study, we investigated the antiproliferative activity of CPT on the multidrug resistant CML cells K562/ADM. Our results demonstrated that CPT decreased the cell viability of K562/ADM cells by inducing cell cycle arrest and apoptosis through suppressing the expression of cyclin D1 and Bcl-2. Further studies indicated that CPT mainly functions at post-transcriptional levels, suggesting the involvement of eukaryotic initiation factor 4E (eIF4E). CPT significantly reduced the expression and activity of eIF4E in K562/ADM cells. Overexpression of eIF4E obvious conferred resistance to the CPT antiproliferation and proapoptotic activity as well as the cyclin D1 and Bcl-2 expressions. Knockdown of eIF4E significantly reduced the inhibitory effect of CPT in K562/ADM, confirming the participation of eIF4E during CPT function process. More importantly, the relative inhibitory efficiency of CPT positively correlated with the reductions on eIF4E in primary CML specimens. These results demonstrated that CPT played antitumor roles in K562/ADM cells by inhibiting the eIF4E regulatory system. Our results provide a novel anticancer mechanism of CPT in human CML cells.
KeywordsCryptotanshinone Chronic myeloid leukemia Cell cycle arrest Apoptosis eIF4E
This work was supported by the Special Foundation for Young Scientists of Zhejiang Chinese Medical University (No. 2011ZR05), National Natural Science Foundation of China (No. 30600280), Research Foundation for Traditional Chinese Medicine of Zhejiang Province (No. 2006Y2003) and the Zhejiang Extremely Key Subject of Chinese and Western Integrative Medicine.
- 3.Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedCrossRefGoogle Scholar
- 8.De Benedetti A, Joshi B, Graff JR, Zimmer SG (1994) CHO cells transformed by the translation factor eIF4E display increased c-myc expression, but require overexpression of Max for tumorigenicity. Mol Cell Differ 2:347–371Google Scholar
- 24.Topisirovic I, Guzman ML, McConnell MJ, Licht JD, Culjkovic B, Neering SJ, Jordan CT, Borden KL (2003) Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Mol Cell Biol 23:8992–9002PubMedCrossRefGoogle Scholar