Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death
Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death
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DOI：
10.1158/0008-5472.can-03-2837
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发表时间：
2004-04-15
期刊：
影响因子：
11.2
通讯作者：
Parsons, PG
中科院分区：
文献类型：
--
作者：
Ogbourne, SM;Suhrbier, A;Parsons, PG
目前皮肤癌治疗的选择包括手术、放射治疗、局部化疗、冷冻手术、刮除和电极化。虽然有效，但手术费用昂贵，不适合某些患者。放射治疗的美容效果很差，而目前的化疗受到治愈率低和治疗方案延长的限制。在这里，我们描述了一种治疗皮肤癌的新型局部化疗药物3-吲哚当归(PEP005)的临床前活性，PEP005是一种从大戟植物中分离出来的疏水二萜酯。每天三次外用42nmol(18杯)的PEP005，治愈了一系列S.C.小鼠肿瘤(B16黑色素瘤、LK2紫外线诱导的鳞状细胞癌和Lewis肺癌；It=-gt；14个肿瘤/组)和人类肿瘤(DO4黑色素瘤、HeLa宫颈癌、PC3和DU145前列腺癌；It=>；4个肿瘤/组)。这种治疗产生了轻微的短期红斑和焦痂形成，但最终导致了极佳的皮肤美容效果。PEP005对一组肿瘤细胞株的LD90为180-220微米。电子显微镜显示，PEP005在体外(230tot)和体内(42nmoL)处理后，迅速导致线粒体肿胀和原发坏死细胞死亡。CR-51的释放、碘化丙啶的摄取以及线粒体染色剂JC1染色显示，PEP005(230微米)作用于体外培养的肿瘤细胞，导致细胞膜的快速扰动和线粒体膜电位的丧失。因此，PEP005作为一种新的局部抗皮肤癌药物应运而生，它具有一种新的作用模式，涉及质膜和线粒体破坏以及原发坏死，最终导致良好的美容效果。
Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodes-sication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 mug) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; it = >14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; it = >4 tumors/group) previously established (5-10 mm(3)) on C57BL/6 or Fox1(nu) mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD90 for PEP005 for a panel of tumor cell lines was 180-220 muM. Electron microscopy showed that treatment with PEP005 both ill vitro (230 tot) and ill vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. Cr-51 release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 muM) treatment of tumor cells ill vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.