Abstract
Furanodienone, a major bioactive constituents of sesquiterpene derived from Rhizoma Curcumae, has been proven to possess the potent anticancer efficacy on human breast cancer cells. Here, we investigated the cytotoxicity of furanodienone on human colorectal carcinoma cell lines in vitro and in vivo, as well as its underlying molecular mechanisms in the induction of apoptosis. In this study, we found that furanodienone significantly inhibited proliferation of RKO and HT-29 cells, induced mitochondrial dysfunction characterized by collapse of mitochondrial transmembrane potential and reduction of ATP level, and promoted the production of reactive oxygen species (ROS) that functions upstream of caspase-dependent apoptosis. The antioxidant N-acetyl cysteine, a ROS scavenger, abolished this apoptosis induced by furanodienone. In addition, furanodienone elevated the expression of p-p38, p-JNK, but decreased p-ERK, as a result of the produced ROS. The specific inhibitors U0126, SP600125 and SB202190 attenuated the expression of MAPKs, and regulated the expression of cleaved caspase-8, -9 and -3. Furthermore, the potential inhibitory effect of furanodienone on CRC cells was also corroborated in mouse xenograft model. In conclusion, the results demonstrated that furanodienone-triggered ROS plays a pivotal role in apoptosis as an upstream molecule-modulating activity of caspases in mitochondrial pathway via stimulating MAPKs signaling pathway. Our finding may provide a novel candidate for development of antitumor drugs targeting on colorectal cancer.
Highlights
Colorectal cancer (CRC) is one of the commonest malignancy and the third leading cause of cancer-related deaths worldwide.[1]
MAPKs play an essential role in diverse cellular programs including modulation the pro and anti-apoptotic proteins located in mitochondria.[23]
SP600125 and SB202190 significantly inhibited the expression of cleaved caspase-8, -9 and -3, while U0126 exhibited an opposite trend. These results suggested that furanodienone-induced Reactive oxygen species (ROS) activated MAPKs signaling pathway, which further elaborated the mitochondria-mediated apoptosis via modulating the caspase-dependent pathway
Summary
Colorectal cancer (CRC) is one of the commonest malignancy and the third leading cause of cancer-related deaths worldwide.[1]. ROS generation involved increasingly in cell proliferation and apoptosis via regulation of MAPK family members comprising of ERK, JNK and p38 MAPK in the action of some chemotherapeutic drugs.[21,22] MAPKs play an essential role in diverse cellular programs including modulation the pro and anti-apoptotic proteins located in mitochondria.[23] For example, in response to oxidative stress, the activation of JNK promotes the apoptotic processes, in a manner of inhibition of Bcl-2 function.[24] degradation of Bcl-2 was found to associate with downregulation of ERK when exposed to oxidative stress.[25] targeting activation of the ROS/MAPK signaling pathway may be a promising strategy for enhancement of antitumor efficacy in the treatment of human cancers
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