title: Selenocysteine derivative overcomes TRAIL resistance in melanoma cells: evidence for ROS-dependent synergism and signaling crosstalk.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as one of the most promising targeted drug for new cancer therapeutics, is limited in clinical application by the evolution of resistance in many cancer cell lines, especially in malignant melanoma. Thus, it is urgently needed to identify chemosensitizers to enhance the apoptotic inducing efﬁcacy of TRAIL and overcome resistance of malignant melanoma cells. Herein, we reported that 3,3'-diselenodipropionic acid (DSeA), a Selenocysteine derivative, could synergistically enhance the growth inhibitory effect of TRAIL on A375 melanoma cells though induction of ROS-dependent apoptosis with involvement of PTEN-mediated Akt inactivation and DNA damage-mediated p53 phosphorylation, which subsequently activated mitochondrial and death receptor apoptotic pathways. Moreover, silencing of p53 down-regulated the expression levels of p53-inducible genes, and effectively blocked the cell apoptosis. Suppression of PI3K signiﬁcantly increased the apoptotic cell death. In contrast, antioxidants effectively reversed the cell apoptosis through regulation of Akt and p53 signaling pathways. Taken together, the combination of DSeA and TRAIL could be a novel strategy to overcome TRAIL resistance in malignant melanoma, and DSeA may be candidates for further evaluation as a chemosensitizer in clinical trails.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong S.A.R., China.
authors.forename: Shanyuan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
authors.affiliation: School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong S.A.R., China.
authors.forename: Yum-Shing
authors.initials: YS
authors.lastname: Wong
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, China.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008545:Melanoma / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D018036:Selenium Compounds / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
chemical_list: C524945:3,3'-diselenodipropionic acid; D000970:Antineoplastic Agents; D000975:Antioxidants; D011422:Propionates; D017382:Reactive Oxygen Species; D018036:Selenium Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human