Does Theobromine Increase the Apoptotic Effect of STI571?

Objective: STI571, a selective tyrosine kinase inhibitor is used in CML chemotherapy. It has limited effects in some cases due to drug resistance and intoxication as other chemotherapeutic agents. Thus, many cancer patients use dietary supplements and herbal extracts for increasing the effectiveness of chemotherapeutic agents. Theobromine, a metabolite of cacao has prooxidant effects and regulates intercellular signaling pathways. The aim of the study is to determine the potential apoptotic effects of STI571 and theobromine on K562 cells, when used alone and in combination. Methods: Inhibitory concentrations of STI571 and theobromine were determined by MTT method. Both agents were applied to the cells at 48 h time period alone and in combination. Caspase activities were assessed colorimetrically. Apoptosis and necrosis were evaluated by using acridine orange/ethidium bromide staining. p<0.05 was considered as statistically significant. Results: Caspase activities increased when both agents administrated alone. Theobromine increased effects of STI571 on caspase activities in time and type dependent manner (p<0.05). Apoptotic cell rates also increased when two agents applied in combination (p<0.05) in time dependent manner. Theobromine also reduced necrotic cell rates. Conclusion: Although there are limited data about the intracellular effects of theobromine, we showed that theobromine has effects on the caspase pathway related apoptotic response carried out by STI571. We believe that this in vitro study will shed light for further researches

Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer

Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target