Cryptotanshinone Inhibits Cancer Cell Proliferation by Suppressing Mammalian Target of Rapamycin–Mediated Cyclin D1 Expression and Rb Phosphorylation

Abstract

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, little is known about its anticancer mechanism. Here, we show that CPT inhibited cancer cell proliferation by arresting cells in G 1 -G 0 phase of the cell cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation. Furthermore, we found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I-or 10% fetal bovine serum-stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration-and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel antiproliferative agent. Cancer Prev Res; 3(8); 1015-25. ©2010 AACR.

Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling

“…CPT has been found to suppress DU145 cell growth by inhibiting STAT3 signaling, mTOR-mediated cyclin D1 expression and Rb phosphorylation. 18,24 In addition, CPT has been found to inhibit HepG2 cell proliferation by arresting cell cycle at the G1 phase in an AMPK-dependent manner. 28 It has been found that CPT leads to caspaseindependent cell death in Rh30 and DU145 cells by activating p38/JNK signaling and inhibiting Erk1/2 signaling in a reactive oxygen species (ROS) dependent manner.…”

“…[18][19][20][21][22][23] In breast carcinoma cells, CPT has been shown to inhibit MCF7 cell proliferation by suppressing mTOR mediated CyclinD1 expression and Rb phosphorylation that lead to MCF7 cell apoptosis by inducing stress in the endoplasmic reticulum (ER). 24,25 However, it is not known whether CPT has any effects on estrogen-stimulated ER signaling and estrogen /ER mediated cancer cell growth.…”

Cryptotanshinone Induces Apoptosis of HL-60 Cells via Mitochondrial Pathway

“…Cryptotanshinone (CPT) is a major constituent of tanshinones, which are extracted from Danshen, and has well-documented antioxidative and anti-inflammatory effects [4]. In addition, recent studies have shown that CPT could induce apoptosis in several kinds of solid tumor [5][6][7], which makes it a potential anticancer agent. However, there is a paucity of research on the effect of CPT on leukemia.…”

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

“…Most recently, data have shown that CPT is the most potent anticancer agent among the extracts of Danshen, by inhibiting proliferation of cancer cells or inducing cell apoptosis (Chen et al, 2010;Chen et al, 2012), but its function on MCF-7 cells still rarely reported. The (Nizamutdinova et al, 2008), therefore, it is important to identify new agents that is effective in breast cancers.…”

“…Until now, researchers have found that CPT down-regulate cyclin D1 expression, which results in cellcycle arrest in G1 phase (Chen et al, 2010), it also inhibits human glioma cell proliferation by suppressing STAT3 signaling (Lu et al, 2013); with regard to apoptosis, CPT sensitizes Fas or ER stress-mediated or enhanced TNF-α-induced apoptosis (Park et al, 2010;Kim et al, 2011;Park et al, 2012).…”