title: HUHS1015 induces necroptosis and caspase-independent apoptosis of MKN28 human gastric cancer cells in association with AMID accumulation in the nucleus.
abstract: The newly synthesized naftopidil analogue HUHS1015 reduced viability of MKN28 and MKN45 human gastric cancer cells in a concentration (0.3-100 μM)-dependent manner, with the potential greater than that for naftopidil. In the cell cycle analysis, HUHS1015 significantly increased the proportion at the subG1 phase of cell cycling in MKN28 cells. In the flow cytometry using propidium iodide (PI) and annexin V, HUHS1015 significantly increased the populations of PI-positive/annexin V-negative and PI-positive/annexin V-positive MKN28 cells, corresponding to primary necrosis and late apoptosis/secondary necrosis, respectively. HUHS1015-induced MKN28 cell death was attenuated by the necroptosis inhibitor Nec-1. In the enzymatic caspase assay, caspase-3, -4, -8, and -9 were not sufficiently activated by HUHS1015. HUHS1015 increased nuclear localization of apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), without affecting expression of the AMID mRNA and protein in MKN28 cells. HUHS1015 caused nuclear fragmentation and condensation in MKN28 cells treated with HUHS1015. Taken together, these results of the present study indicate that HUHS1015 induces both necroptosis and caspase-independent apoptosis of MKN28 cells, possibly the latter effect being due to AMID accumulation in the nucleus.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kaku
authors.forename: Ayako
authors.initials: A
authors.lastname: Tsuchiya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. tomoyuki@hyo-med.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced*; D011412:Propanolamines / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C586405:1-(2-(2-methoxyphenylamino)ethylamino)-3-(naphthalene-1-yloxy)propan-2-ol; C462504:ferroptosis suppressor protein 1, human; D000814:Aniline Compounds; D017304:Annexin A5; D051017:Apoptosis Regulatory Proteins; D024101:Mitochondrial Proteins; D011412:Propanolamines; D020169:Caspases