title: Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells.
abstract: The anticancer effects of fisetin, a dietary agent, are largely unknown against human gastric cancer. Herein, we investigated the mechanisms of fisetin-induced inhibition of growth and survival of human gastric carcinoma AGS and SNU-1 cells. Fisetin (25-100 μM) caused significant decrease in the levels of G1 phase cyclins and CDKs, and increased the levels of p53 and its S15 phosphorylation in gastric cancer cells. We also observed that growth suppression and death of non-neoplastic human intestinal FHs74int cells were minimally affected by fisetin. Fisetin strongly increased apoptotic cells and showed mitochondrial membrane depolarization in gastric cancer cells. DNA damage was observed as early as 3 h after fisetin treatment which was accompanied with gamma-H2A.X(S139) phosphorylation and cleavage of PARP. Fisetin-induced apoptosis was observed to be independent of p53. DCFDA and MitoSOX analyses showed an increase in mitochondrial ROS generation in time- and dose-dependent fashion. It also increased cellular nitrite and superoxide generation. Pre-treatment with N-acetyl cysteine (NAC) inhibited ROS generation and also caused protection from fisetin-induced DNA damage. The formation of comets were observed in only fisetin treated cells which was blocked by NAC pre-treatment. Further investigation of the source of ROS, using mitochondrial respiratory chain (MRC) complex inhibitors, suggested that fisetin caused ROS generation specifically through complex I. Collectively, these results for the first time demonstrated that fisetin possesses anticancer potential through ROS production most likely via MRC complex I leading to apoptosis in human gastric carcinoma cells. © 2016 Wiley Periodicals, Inc.
authors.affiliation: School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India.
authors.forename: Akash
authors.initials: A
authors.lastname: Sabarwal
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, Colorado.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India.|Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rana P
authors.initials: RP
authors.lastname: Singh
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D044948:Flavonols; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C017875:fisetin
keywords: ROS; apoptosis; fisetin; gastric cancer; mitochondrial respiratory chain complex I