The protein kinase C agonist PEP005 (ingenol 3-angelate) in the treatment of human cancer: a balance between efficacy and toxicity.
The protein kinase C agonist PEP005 (ingenol 3-angelate) in the treatment of human cancer: a balance between efficacy and toxicity.
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DOI：
10.3390/toxins2010174
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发表时间：
2010-01
期刊：
影响因子：
4.2
通讯作者：
Bruserud O
中科院分区：
文献类型：
--
作者：
Ersvaer E;Kittang AO;Hampson P;Sand K;Gjertsen BT;Lord JM;Bruserud O
二萜酯吲哚-3-天使酸酯(简称PEP005)是从植物一品红中提取的。虎眼草粗提物在局部使用时会引起局部毒性和一过性炎症，已被用于治疗尖锐湿疣、皮肤角化症和皮肤癌。PEP005是一种广泛的经典(α，β，γ)和新型(δ，ε，η，θ)蛋白激酶C同工酶激活剂。这种药物的直接促凋亡作用已在几种恶性细胞中被证明，包括黑色素瘤细胞系和原代人类急性髓系白血病细胞。在杀死黑色素瘤细胞所需的微摩尔浓度下，这种药物会导致PKC不依赖的继发性坏死。相反，对白血病细胞的杀伤发生在纳摩尔范围内，需要蛋白激酶Cδ(PKCδ)的激活，并与PKCδ从细胞质到核膜的转位特异性相关。然而，除了这种促凋亡作用外，该制剂似乎还具有免疫刺激作用，包括：(I)增加恶性肿瘤细胞释放趋化因子；(Ii)激活的T细胞，包括来自化疗引起的淋巴细胞减少患者的T细胞，普遍增加增殖和细胞因子的释放；(Iii)局部应用中性粒细胞，增加抗体依赖的细胞毒性；(Iv)在动物模型中CD8+T细胞产生特异性的抗癌免疫反应。已发表的研究主要描述了该药物在体外研究或局部应用后的效果，在可能将该药物用于皮肤癌以外的恶性肿瘤治疗之前，需要仔细评估全身给药后的毒性。
The diterpene ester ingenol-3-angelate (referred to as PEP005) is derived from the plant Euphorbia peplus. Crude euphorbia extract causes local toxicity and transient inflammation when applied topically and has been used in the treatment of warts, skin keratoses and skin cancer. PEP005 is a broad range activator of the classical (α, β, γ) and novel (δ, ε, η, θ) protein kinase C isoenzymes. Direct pro-apoptotic effects of this drug have been demonstrated in several malignant cells, including melanoma cell lines and primary human acute myelogenous leukemia cells. At micromolar concentrations required to kill melanoma cells this agent causes PKC-independent secondary necrosis. In contrast, the killing of leukemic cells occurs in the nanomolar range, requires activation of protein kinase C δ (PKCδ) and is specifically associated with translocation of PKCδ from the cytoplasm to the nuclear membrane. However, in addition to this pro-apoptotic effect the agent seems to have immunostimulatory effects, including: (i) increased chemokine release by malignant cells; (ii) a general increase in proliferation and cytokine release by activated T cells, including T cells derived from patients with chemotherapy-induced lymphopenia; (iii) local infiltration of neutrophils after topical application with increased antibody-dependent cytotoxicity; and (iv) development of specific anti-cancer immune responses by CD8+ T cells in animal models. Published studies mainly describe effects from in vitro investigations or after topical application of the agent, and careful evaluation of the toxicity after systemic administration is required before the possible use of this agent in the treatment of malignancies other than skin cancers.
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影响因子：
4.8
作者：
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通讯作者：
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