RRC ID 51579
著者 Kaku Y, Tsuchiya A, Shimizu T, Tanaka A, Nishizaki T.
タイトル HUHS1015 Suppresses Colonic Cancer Growth by Inducing Necrosis and Apoptosis in Association with Mitochondrial Damage.
ジャーナル Anticancer Res
Abstract BACKGROUND:The newly-synthesized naftopidil analog HUHS1015 suppresses tumor growth and induces apoptosis of cells from a variety of cancer types. The present study was conduced to assess the effect of HUHS1015 on human colonic cancer cells and to clarify the underlying mechanism.
RESULTS:HUHS1015 reduced cell viability of Caco-2 and CW2 human colonic cancer cell lines in a concentration (0.3-100 mM)-dependent manner. HUHS1015 increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in both cell lines. In flow cytometry using propidium iodide and annexin V, HUHS1015 significantly increased the populations of cells undergoing primary necrosis, early apoptosis, and late apoptosis/secondary necrosis in both cell lines. In the cell-cycle analysis, HUHS1015 increased the proportion of the sub-G1 phase of cell, which corresponds to apoptotic cells. HUHS1015 perturbed the mitochondrial membrane potential and reduced the intracellular ATP level. HUHS1015 activated caspases 3, -4, -8, and -9, particularly caspase-3. HUHS1015 promoted cytochrome c release from the mitochondria. HUHS1015 significantly inhibited tumor growth in mice inoculated with CW2 cells.
CONCLUSION:HUHS1015 induces necrosis by lowering the intracellular ATP level in association with mitochondrial damage and caspase-dependent apoptosis. This occurs in part by stimulating cytochrome c release from the mitochondria to activate caspase-9 followed by the effector caspase-3, responsible for suppression of colonic cancer proliferation in the mouse xenograft model.
巻・号 36(1)
ページ 39-48
公開日 2016-1-1
PII 36/1/39
PMID 26722026
MeSH Adenosine Triphosphate / metabolism Aniline Compounds / pharmacology* Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Caco-2 Cells Caspases / metabolism Cell Proliferation / drug effects* Colonic Neoplasms / drug therapy* Colonic Neoplasms / metabolism Colonic Neoplasms / pathology Cytochromes c / metabolism Dose-Response Relationship, Drug Enzyme Activation G1 Phase Cell Cycle Checkpoints / drug effects Humans Male Membrane Potential, Mitochondrial / drug effects Mice, Inbred BALB C Mice, Nude Mitochondria / drug effects* Mitochondria / metabolism Mitochondria / pathology Necrosis Propanolamines / pharmacology* Time Factors Tumor Burden / drug effects Xenograft Model Antitumor Assays
IF 1.994
引用数 3
リソース情報
ヒト・動物細胞 CACO-2(RCB0988) CW-2(RCB0778)