title: Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway.
abstract: 5-Fluorouracil (5-FU)-based chemotherapy as a first-line treatment is quite limited, because of its inefficiency and clinical resistance to it. The search for chemosensitizers that could augment its efficiency and overcome the drug resistance to 5-FU has kindled great interest among scientists. Selenocystine (SeC), a naturally occurring selenoamino acid, displayed broad-spectrum anticancer activity in our previous studies. This study demonstrates that SeC acts as an effective enhancer of 5-FU-induced apoptosis in A375 human melanoma cells through induction of mitochondria-mediated apoptosis with the involvement of DNA damage-mediated p53 phosphorylation and ERK inactivation. Pretreatment of the cells with SeC significantly enhanced 5-FU-induced loss of mitochondrial membrane potential (∆ψm) by regulating the expression levels of Bcl-2 family proteins. SeC and 5-FU in combination also triggered cell oxidative stress through regulation of the intracellular redox system and led to DNA damage and inactivation of ERK and AKT. Moreover, inhibitors of ERK and AKT effectively enhanced the apoptotic cell death induced by the combined treatment. However, pretreatment of the cells with glutathione reversed the apoptosis induced by SeC and 5-FU and recovered the expression of ERK and AKT inactivation, which revealed the important role of reactive oxygen species in cell apoptosis and regulation of ERK and AKT pathways. Taken together, our results suggest that a strategy of using SeC and 5-FU in combination could be a highly efficient way to achieve anticancer synergism.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Cundong
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Yum-Shing
authors.initials: YS
authors.lastname: Wong
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. Electronic address: tzhwj@jnu.edu.cn.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. Electronic address: tchentf@jnu.edu.cn.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage / Q000502:physiology; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016566:Organoselenium Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species
chemical_list: D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C009226:selenocystine; D003553:Cystine; D005472:Fluorouracil
keywords: 5-Fluorouracil; Apoptosis; Chemosensitization; Free radicals; Selenocystine; Synergy