Cryptotanshinone induces ER stress-mediated apoptosis in HepG2 and MCF7 cells

The endoplasmic reticulum (ER) is a central organelle in eukaryotic cells that functions in protein synthesis and maturation, and also functions as a calcium storage organelle. Perturbation of ER functions leads to ER stress, which has been previously associated with a broad variety of diseases. ER stress is generally regarded as compensatory, but prolonged ER stress can activate apoptotic pathways in damaged cells. For this reason, pharmacological interventions that effectively enhance tumor death through ER stress have been the subject of a great deal of attention for anti-cancer therapy. Cryptotanshinone, the major active constituent isolated from the root of Salvia miltiorrhiza Bunge, has been recently evaluated for its anti-cancer activity, but the molecular mechanisms underlying these activities remain poorly understood. In particular, it remains completely unknown as to whether or not cryptotanshinone can induce ER stress. Herein, we identify cryptotanshinone as a potent stimulator of ER stress, leading to apoptosis in many cancer cell lines, including HepG2 hepatoma and MCF7 breast carcinoma, and also demonstrate that mitogen-activated protein kinases function as mediators in this process. Reactive oxygen species generated by cryptotanshinone have been shown to play a critical role in ER stress-induced apoptosis. Cryptotanshinone also evidenced sensitizing effects to a broad range of anti-cancer agents including Fas/Apo-1, TNF-α, cisplatin, etoposide or 5-FU through inducing ER stress, highlighting the therapeutic potential in the treatment of human hepatoma and breast cancer.