title: Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway.
abstract: Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Chang Bing Show Chwan Memorial Hospital, Lugang Town, Changhua County, Taiwan.|Liberal Arts Center, Da-Yeh University, Changhua, Taiwan.
authors.forename: Ming-Te
authors.initials: MT
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chia-Liang
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Biological Sciences, University of California Davis, Davis, CA, USA.
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Cheng
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chu-Liang
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan. hyhsien@csmu.edu.tw.|Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan. hyhsien@csmu.edu.tw.|Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan. hyhsien@csmu.edu.tw.
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Hsieh
authors.affiliation: School of Medicine, Tzu Chi University, Hualien, Taiwan. abi0918@outlook.com.|Department of Internal Medicine, Division of Nephrology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan. abi0918@outlook.com.
authors.forename: Jen-Pi
authors.initials: JP
authors.lastname: Tsai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D005419:Flavonoids; D044948:Flavonols; D010671:Phenylurea Compounds; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D009536:Niacinamide; D000077157:Sorafenib; D053148:Caspase 3; D053181:Caspase 8; C017875:fisetin
keywords: Apoptosis; Cervical cancer; Fisetin; Mitochondrial membrane potential; Sorafenib