Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 3. Inhibitory effect of SkQ1 on tumor development from p53-deficient cells
Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 3. Inhibitory effect of SkQ1 on tumor development from p53-deficient cells
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DOI：
10.1134/s0006297908120031
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发表时间：
2008-12-01
影响因子：
2.8
通讯作者：
Skulachev, V. P.
中科院分区：
文献类型：
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作者：
Agapova, L. S.;Chernyak, B. V.;Skulachev, V. P.
有人提出，线粒体活性氧（ROS）的水平增加，介导执行的衰老程序的生物体，也可能是肿瘤转化和肿瘤发生的关键。使用新的靶向抗氧化剂SkQ 1（10-（6 '-plastoquinonyl）decyltriphenylphosphonium）解决了该提议，该抗氧化剂以纳摩尔浓度清除线粒体中的ROS。我们发现，饮食中补充SkQ 1（每天5 nmol/kg）抑制了p53（-/-）小鼠肿瘤（主要是淋巴瘤）的自发发展。相同剂量的SkQ 1抑制裸鼠人结肠癌HCT 116/p53（-/-）移植瘤的生长。人HPV-16相关宫颈癌SiHa的肿瘤异种移植物的生长仅受到SkQ 1的轻微影响，但荷瘤动物的存活率增加。还显示SkQ 1抑制肿瘤细胞增殖，这在培养的HCT 116 p53（-/-）和SiHa细胞中得到证实。此外，SkQ 1在体外诱导多种肿瘤细胞分化。在上皮肿瘤细胞中观察到协调的SkQ 1启动的细胞形状、细胞骨架组织和E-钙粘蛋白阳性细胞间接触的变化。在Ras和SV 40转化的成纤维细胞中，发现SkQ 1启动恶性类型的形态转化逆转，恢复肌动蛋白应力纤维和粘着斑接触。SkQ 1抑制Matrigel植入物中的血管生成，表明线粒体ROS可能对肿瘤血管生成很重要。然而，这种作用在HCT 116/p53（-/-）肿瘤异种移植物中不太明显。我们还表明，SkQ 1和相关的带正电荷的抗氧化剂是P-糖蛋白多药耐药泵的底物。在携带突变形式的p53的HCT 116异种移植物的情况下，发现SkQ 1的较低的抗肿瘤作用和减少的细胞内积累可能与较高水平的P-糖蛋白有关。传统抗氧化剂N-乙酰-L-半胱氨酸（NAC）对肿瘤生长和肿瘤细胞表型的作用与SkQ 1相似，但需要比SkQ 1高1，000，000倍的NAC剂量。SkQ 1的极高效率，与其在线粒体膜中的积累有关，表明线粒体ROS的产生至少在一些动物模型中对肿瘤发生至关重要。
It was proposed that increased level of mitochondrial reactive oxygen species (ROS), mediating execution of the aging program of an organism, could also be critical for neoplastic transformation and tumorigenesis. This proposal was addressed using new mitochondria-targeted antioxidant SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) that scavenges ROS in mitochondria at nanomolar concentrations. We found that diet supplementation with SkQ1 (5 nmol/kg per day) suppressed spontaneous development of tumors (predominantly lymphomas) in p53(-/-) mice. The same dose of SkQ1 inhibited the growth of human colon carcinoma HCT116/p53(-/-) xenografts in athymic mice. Growth of tumor xenografts of human HPV-16-associated cervical carcinoma SiHa was affected by SkQ1 only slightly, but survival of tumor-bearing animals was increased. It was also shown that SkQ1 inhibited the tumor cell proliferation, which was demonstrated for HCT116 p53(-/-) and SiHa cells in culture. Moreover, SkQ1 induced differentiation of various tumor cells in vitro. Coordinated SkQ1-initiated changes in cell shape, cytoskeleton organization, and E-cadherin-positive intercellular contacts were observed in epithelial tumor cells. In Ras- and SV40-transformed fibroblasts, SkQ1 was found to initiate reversal of morphological transformation of a malignant type, restoring actin stress fibers and focal adhesion contacts. SkQ1 suppressed angiogenesis in Matrigel implants, indicating that mitochondrial ROS could be important for tumor angiogenesis. This effect, however, was less pronounced in HCT116/p53(-/-) tumor xenografts. We have also shown that SkQ1 and related positively charged antioxidants are substrates of the P-glycoprotein multidrug resistance pump. The lower anti-tumor effect and decreased intracellular accumulation of SkQ1, found in the case of HCT116 xenografts bearing mutant forms of p53, could be related to a higher level of P-glycoprotein. The effects of traditional antioxidant N-acetyl-L-cysteine (NAC) on tumor growth and tumor cell phenotype were similar to the effects of SkQ1 but more than 1,000,000 times higher doses of NAC than those of SkQ1 were required. Extremely high efficiency of SkQ1, related to its accumulation in the mitochondrial membrane, indicates that mitochondrial ROS production is critical for tumorigenesis at least in some animal models.