Afaq Farrukh, Saleem Mohammad, Aziz Moammir Hasan, Mukhtar Hasan
Department of Dermatology, Medical Sciences Centre, University of Wisconsin, Madison, WI 53706, USA.
Toxicol Appl Pharmacol. 2004 Mar 15;195(3):361-9. doi: 10.1016/j.taap.2003.09.027.
Oleandrin, derived from the leaves of Nerium oleander, has been shown to possess anti-inflammatory and tumor cell growth-inhibitory effects. Here, we provide evidence that oleandrin could possess anti-tumor promoting effects. We determined the effect of topical application of oleandrin to CD-1 mice against l2-O-tetradecanoylphorbol-13-acetate (TPA), a widely studied skin tumor promoter, -induced conventional and novel markers of skin tumor promotion. Topical application of oleandrin (2 mg per mouse) 30 min before TPA (3.2 nmol per mouse) application onto the skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in cutaneous edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and ODC and cyclooxgenase-2 (COX-2) protein expression. In search for novel markers of skin tumor promotion, we found that TPA application to mouse skin resulted, as an early event, in an increased expression of phosphatidyinositol 3-kinase (PI3K), phosphorylation of Akt at threonine308 and activation of nuclear factor kappa B (NF-kappaB). Topical application of oleandrin before TPA application to mouse skin resulted in significant reduction in TPA-induced expression of PI3K and phosphorylation of Akt, and inhibition of NF-kappaB activation. NF-kappaB is a eukaryotic transcription factor that is critically involved in regulating the expression of specific genes that participate in inflammation, apoptosis and cell proliferation. Employing Western blot analysis, we found that oleandrin application to mouse skin resulted in inhibition of TPA-induced activation of NF-kappaB, IKKalpha and phosphorylation and degradation of IkappaBalpha. Our data suggest that oleandrin could be a useful anti-tumor promoting agent because it inhibits several biomarkers of TPA-induced tumor promotion in an in vivo animal model. One might envision the use of chemopreventive agents such as oleandrin in an emollient or patch for chemoprevention or treatment of skin cancer.
夹竹桃麻素源自夹竹桃的叶子，已被证明具有抗炎和抑制肿瘤细胞生长的作用。在此，我们提供证据表明夹竹桃麻素可能具有抗肿瘤促进作用。我们测定了将夹竹桃麻素局部应用于CD - 1小鼠，以对抗12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA，一种广泛研究的皮肤肿瘤促进剂）诱导的皮肤肿瘤促进的传统和新型标志物的效果。在将TPA（每只小鼠3.2 nmol）涂抹于皮肤前30分钟，局部应用夹竹桃麻素（每只小鼠2 mg），以时间依赖性方式显著抑制了TPA介导的皮肤水肿和增生、表皮鸟氨酸脱羧酶（ODC）活性以及ODC和环氧化酶 - 2（COX - 2）蛋白表达的增加。在寻找皮肤肿瘤促进的新型标志物时，我们发现将TPA应用于小鼠皮肤会作为早期事件导致磷脂酰肌醇3 -激酶（PI3K）表达增加、苏氨酸308位点的Akt磷酸化以及核因子κB（NF - κB）激活。在将TPA应用于小鼠皮肤前局部应用夹竹桃麻素，导致TPA诱导的PI3K表达和Akt磷酸化显著降低，并抑制NF - κB激活。NF - κB是一种真核转录因子，在调节参与炎症、细胞凋亡和细胞增殖的特定基因的表达中起关键作用。采用蛋白质印迹分析，我们发现将夹竹桃麻素应用于小鼠皮肤可抑制TPA诱导的NF - κB、IKKα激活以及IkappaBα的磷酸化和降解。我们的数据表明夹竹桃麻素可能是一种有用的抗肿瘤促进剂，因为它在体内动物模型中抑制了TPA诱导的肿瘤促进的几种生物标志物。人们可以设想在润肤剂或贴剂中使用夹竹桃麻素等化学预防剂来进行皮肤癌的化学预防或治疗。
