title: Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer             MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy.
abstract: The outcome of producing apoptotic defects in cancer cells is the primary             obstacle that limits the therapeutic efficacy of anticancer agents, and hence             the development of novel agents targeting novel non-canonical cell death pathways             has become an imperative mission for clinical research. Fisetin (3,3',4',7-tetrahydroxyflavone)             is a naturally occurring flavonoid commonly found in fruits and vegetables. In             this study, we investigated the potential anticancer effects of fisetin on breast             cancer cells. The result showed fisetin induced higher cytotoxicity in human breast             cancer MCF-7 than in MDA-MB-231 cells otherwise it did not exert any detectable             cytotoxicity in non-tumorigenic MCF-10A cells. We found fisetin can trigger a             novel form of atypical apoptosis in caspase-3-deficient MCF-7 cells, which was             characterized by several apoptotic features, including plasma membrane rupture,             mitochondrial depolarization, activation of caspase-7, -8 and -9, and PARP cleavage;             however, neither DNA fragmentation and phosphotidylserine (PS) externalization             was observed. Although p53 was also activated by fisetin, the fisetin-induced             apoptosis was not rescued by the p53 inhibitor pifithrin-α. In contrast, the fisetin-induced             apoptosis was abrogated by pan-caspase inhibitor z-VAD-fmk. Furthermore, inhibition             of autophagy by fisetin was shown as additional route to prompt anticancer activity             in MCF-7 cells. These data allow us to propose that fisetin appears as a new potential             anticancer agent which can be applied to develop a clinical protocol of human             breast cancers.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Pei-Ming
authors.initials: PM
authors.lastname: Yang
authors.forename: Ho-Hsing
authors.initials: HH
authors.lastname: Tseng
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Peng
authors.forename: Wen-Shu
authors.initials: WS
authors.lastname: Chen
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Chiu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology*; D053148:Caspase 3 / Q000172:deficiency*; D053179:Caspase 7 / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D005419:Flavonoids; D044948:Flavonols; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; C017875:fisetin