論文 - 詳細
RRC ID | 51579 |
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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) |