Cinnamaldehyde induces endogenous apoptosis of the prostate cancer-associated fibroblasts via interfering the Glutathione-associated mitochondria function.

Cinnamaldehyde (CA) is an essential component of cinnamon that has been shown to exhibit anti-tumor effects through growth inhibition and induction of apoptosis in cancer cells. We have previously shown that CA could interfere with myeloid-derived suppressor cells (MDSCs), leading to cancer growth inhibition. In addition, recent studies have demonstrated that cancer-associated fibroblasts (CAFs) promote cancer development in different ways. However, the effect of CA in CAFs has not been studied. In this study, we investigated the effect and mechanism of action of CA in prostate CAFs. We found that CA induced cell cycle arrest and apoptosis in prostate CAFs via the intrinsic pathway. This was due to the decrease in mitochondrial membrane potential (∆Mψ), increased level of intracellular reactive oxygen species (ROS), and calcium ion (Ca2+). In addition, protein expression analysis showed an increase in the expression levels of cytochrome c, bax, cleaved caspase 3 and cleaved PARP, and a decrease in the expression levels of Bcl-2, caspase 9, PARP, and DEF-45. Interestingly, reduced glutathione (GSH) rescued CAFs from CA-induced cell apoptosis, demonstrating that generation of ROS is critical for this effect. From this study, we see that CA has the ability to inhibit growth of CAFs and is therefore a potential cancer therapeutic target.