Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: Implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species
Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: Implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species
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DOI：
10.1158/0008-5472.can-03-1670
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发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Kizaki, M
中科院分区：
文献类型：
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作者：
Ito, K;Nakazato, T;Kizaki, M
辣椒素（N-香草基-8-甲基-1-壬烯酰胺）是一种存在于辛辣水果中的高香草酸衍生物。一些研究者报道了辣椒素抑制与促进癌症相关的事件的能力。然而，辣椒素对人类白血病细胞的影响从未被研究过。我们研究了辣椒素对白血病细胞在体外和体内的影响，并进一步研究了辣椒素诱导髓性白血病细胞凋亡的分子机制。辣椒素通过诱导G（0）-G（1）期细胞周期阻滞和凋亡抑制白血病细胞的生长，但对正常骨髓单个核细胞无明显影响。辣椒素诱导的细胞凋亡与细胞内活性氧产生的升高有关。有趣的是，辣椒素敏感性白血病细胞具有野生型p53，导致辣椒素处理后p53的Ser-15残基磷酸化。反义寡核苷酸对p53表达的抑制显著减弱辣椒素诱导的细胞周期阻滞和凋亡。预处理的抗氧化剂N-乙酰-L-半胱氨酸和过氧化氢酶，但不是超氧化物歧化酶，完全抑制辣椒素诱导的细胞凋亡，抑制丝氨酸-15残基的p53磷酸化。此外，辣椒素在体内使用NOD/SCID小鼠有效地抑制肿瘤生长并诱导细胞凋亡，而没有毒性作用。我们的结论是辣椒素有潜力作为一种新的治疗剂用于治疗白血病。
Capsaicin (N-vanillyl-8-methyl-1-nonenamide) is a homovanillic acid derivative found in pungent fruits. Several investigators have reported the ability of capsaicin to inhibit events associated with the promotion of cancer. However, the effects of capsaicin on human leukemic cells have never been investigated. We investigated the effects of capsaicin on leukemic cells in vitro and in vivo and further examined the molecular mechanisms of capsaicin-induced apoptosis in myeloid leukemic cells. Capsaicin suppressed the growth of leukemic cells, but not normal bone marrow mononuclear cells, via induction of G(0)-G(1) phase cell cycle arrest and apoptosis. Capsaicin-induced apoptosis was in association with the elevation of intracellular reactive oxygen species production. Interestingly, capsaicin-sensitive leukemic cells were possessed of wild-type p53, resulting in the phosphorylation of p53 at the Ser-15 residue by the treatment of capsaicin. Abrogation of p53 expression by the antisense oligonucleotides significantly attenuated capsaicin-induced cell cycle arrest and apoptosis. Pretreatment with the antioxidant N-acetyl-L-cystein and catalase, but not superoxide dismutase, completely inhibited capsaicin-induced apoptosis by inhibiting phosphorylation of Ser-15 residue of p53. Moreover, capsaicin effectively inhibited tumor growth and induced apoptosis in vivo using NOD/SCID mice with no toxic effects. We conclude that capsaicin has potential as a novel therapeutic agent for the treatment of leukemia.