## 4 Anti-Cancer Activities of Tanshinones
### Anti-Proliferation and Pro-Apoptosis
#### 4.1.3 Cryptotanshinone (CT)  
Anti-proliferation and pro-apoptosis activities of CT have been reported in multiple cancer cells including cervical cancer, cholangiocarcinoma, melanoma, rhabdomyosarcoma and leukemia [178,179,180,181,182]. 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 [178,179,180]. CT at 2.5-40 \(\upmu\)M inhibited the growth of human Rh30 rhabdomyosarcoma and DU 145 prostate cancer cells in a concentration-dependent manner, in association with suppression of mTOR pathway, decreased cyclin D\({}_{1}\) expression and RB phosphorylation. Constitutive activation of mTOR attenuated CT-induceddecrease of cyclin D\({}_{1}\) expression and RB phosphorylation as well as cell growth inhibition, suggesting mTOR pathway as an important target [181]. Similarly, CT at 5-20 uM induced cell cycle arrest and apoptosis in drug-resistant leukemia K562/ADM cells, in association with down-regulation of cyclin D\({}_{1}\) and Bcl-2. The inhibition of cyclin D\({}_{1}\) and Bcl-2 happened on post-transcriptional level accompanied by inhibiting eukaryotic initiation factor 4E (eIF4E), in that over-expression of eIF4E attenuated the inhibitory effect of CT [182].  
Through screening more than 3000 herbal products, [PERSON] _et al._[183] identified CT as a selective inhibitor of STAT3, a member of the signal transducer and activator of transcription (STAT) family [184]. Overexpression and constitutive activation of STAT3 promote tumorigenesis by transcriptionally up-regulating its down-stream targets such as cyclin D\({}_{1}\), survivin and VEGF, which are involved in proliferation, apoptosis and angiogenesis [185; 186; 187; 188]. CT at 7 uM inhibited DU145 prostate cancer cell (STAT3 highly active) growth accompanied by inhibition of STAT3 Tyr705 phosphorylation and the expression of down-stream targets. Mechanism investigation showed that CT suppressed STAT3 dimerization, nuclear translocation and DNA binding [183]. Compared with CT, TIIA at the same concentration range did not inhibit STAT3 activity in this study [183]. However, a previous study reported that TIIA at 3.4-27 uM could inhibit the constitutive activation of STAT3 in rat C6 glioma cells [189]. The different cell types (human prostate cancer _vs._ rat glioma) might be a possible explanation about the discrepancy between the two cell culture studies. Since CT converts to TIIA _in vivo_, the anti-cancer efficacy in animal models are likely the combined effect of CT with TIIA.  
In addition, [PERSON] _et al._[190] reported that CT at 1-10 uM sensitized DU 145 cells to Fas-mediated apoptosis through inhibiting Fas-mediated Bcl-2 expression. Many cancer cells express death-receptor Fas on their membranes, however, some are resistant to Fas-mediated apoptosis because activation of Fas can simultaneously up-regulate the anti-apoptosis protein Bcl-2 in these cells through JNK and p38 MAPK kinase pathways. Co-treatment with CT significantly blocked Fas-induced activation of these kinases and consequently inhibited Fas-induced up-regulation of Bcl-2, and then sensitized Fas-mediated apoptosis in these cells.