Abstract
Simple SummaryTaurine (Tau) has been shown to inhibit cancer growth. However, the mechanisms that underlie the growth-inhibitory effects of Tau remain obscure in both colon and breast cancer. In parallel, N-bromotaurine (TauNHBr) and a stable active bromine molecule, bromamine T (BAT), appear to exert strong anti-inflammatory effects. To our knowledge, this is the first study that evaluates the anti-cancer effects of BAT and its underlying mechanisms. To gain a comprehensive picture of the cytotoxic effect of BAT on colon and breast cancer, we compared its effect with that of Tau. Our data support that BAT exerts a superior anti-cancer effect than Tau, through the induction of cell death, probably due to the activation of distinct mitogen-activated protein kinase (MAPK) family members. Interestingly, BAT inhibits colon carcinogenesis in vivo to a greater extent than Tau. Our data significantly add to the use of BAT as a novel therapeutic modality in colon and breast cancer.Background: Taurine (Tau) ameliorates cancer pathogenesis. Researchers have focused on the functional properties of bromamine T (BAT), a stable active bromine molecule. Both N-bromotaurine (TauNHBr) and BAT exert potent anti-inflammatory properties, but the landscape remains obscure concerning the anti-cancer effect of BAT. Methods: We used Crystal Violet, colony formation, flow cytometry and Western blot experiments to evaluate the effect of BAT and Tau on the apoptosis and autophagy of cancer cells. Xenograft experiments were used to determine the in vivo cytotoxicity of either agent. Results: We demonstrated that both BAT and Tau inhibited the growth of human colon, breast, cervical and skin cancer cell lines. Among them, BAT exerted the greatest cytotoxic effect on both RKO and MDA-MB-468 cells. In particular, BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK½), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK½), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. In contrast, Tau exerted its cytotoxic effect by upregulating JNK½ forms, thus triggering mitochondrial apoptosis in RKO cells. Accordingly, colon cancer growth was impaired in vivo. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities.
Highlights
Colorectal cancer (CRC) is one of the most prevalent carcinomas worldwide [1], with the BRAF oncogene being mutated in 5–8% of cases [2,3]
Human colon cancer cells (RKO, Caco2, HT-29), human breast cancer cells (MDA-MB231, MDA-MB-468), human skin cancer cells (WM-164), and human cervical cancer cells (HeLa) were incubated with serial dilutions of bromamine T (BAT) (Figure 1) or Tau (Figure 2) for 24–72 h and the Crystal Violet assay was performed. Both BAT and Tau were cytotoxic in all cancer cells in a concentration and time-dependent manner (Figures 1 and 2), with the most promising results arising in RKO cells
The beneficial impact of BAT surpassed that of Tau on cancer cell proliferation in a concentration- and time-dependent manner (Tables S1–S7)
Summary
Colorectal cancer (CRC) is one of the most prevalent carcinomas worldwide [1], with the BRAF oncogene being mutated in 5–8% of cases [2,3]. Identifying the mechanism underlying cancer cell resistance elicited by BRAF inhibitors is critical for the development of more effective therapies [4,5,6] In this context, various chemotherapeutic agents have been proposed to exert their anti-tumor effect though irreversible DNA damage caused by reactive oxygen species (ROS) accumulation [7,8], since cancer cells are characterized by a higher metabolic rate than normal cells, rendering them more vulnerable to ROS-mediated insults and cell death pathways [9]. BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK 12 ), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK 12 ), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities
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