Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E

Abstract

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.

Cryptotanshinone suppresses the proliferation and induces the apoptosis of pancreatic cancer cells via the STAT3 signaling pathway

“…The results from a study by Chen et al suggested that CPT is a potential drug for the treatment and prevention of human lung cancer (25). The results of our previous study indicated that CPT remained potent in tumor cells with an MDR phenotype, suggesting its potential application in cancer exhibiting a high level of chemotherapeutic resistance (12). In the present study, CPT significantly decreased the viability of the BxPC-3 pancreatic cancer cells via the induction of apoptosis and cell cycle arrest, suggesting the possibility of CPT being developed as an agent for pancreatic cancer therapy.…”

“…Extensive investigations have indicated that CPT may inhibit the proliferation of cancer cells in vitro and reduce the growth and metastases of tumors in vivo (11)(12)(13). CPT inhibits the function of STAT3 though inhibiting dimerization in DU145 prostate cancer cells (14).…”

Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

“…Anti-proliferation and pro-apoptosis activities of CT have been reported in multiple cancer cells including cervical cancer, cholangiocarcinoma, melanoma, rhabdomyosarcoma and leukemia [178–182]. CT-induced cell cycle arrest and apoptosis were in association with up-regulation of P53 and P21, and decreases of cyclin A 1 , cyclin B 1 , cdc2 and survivin [178–180].…”

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

“…In prostate cancer cells, CPT induced cell apoptosis by suppressing mammalian target of rapamycin (mTOR)-mediated cyclin D1 expression [12] and inhibiting Stat3 activity [13]. In myeloid leukemia cells, CPT induced apoptosis by inhibiting the eukaryotic initiation factor 4E (eIF4E) regulatory system [14] and through ROS-dependent activation of caspase-8 and p38 MAPK [15]. While the anticancer activities of CPT against diverse types of cancer cells have been reported, the efficacy and molecular mechanisms of CPT remain unclear in colorectal cancer cells.…”