Reduction of cancer cell viability by synergistic combination of photodynamic treatment with the inhibition of the Id protein family
Reduction of cancer cell viability by synergistic combination of photodynamic treatment with the inhibition of the Id protein family
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DOI：
10.1016/j.jphotobiol.2017.11.038
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发表时间：
2018-01-01
影响因子：
5.4
通讯作者：
Cabrele, Chiara
中科院分区：
文献类型：
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作者：
Roschger, Cornelia;Verwanger, Thomas;Cabrele, Chiara
DNA结合和细胞分化（Id）蛋白的抑制剂是螺旋环-螺旋转录因子家族的主要负调控因子，在发育过程中以及在血管疾病和癌症中发挥关键作用。事实上，损害癌细胞中的Id蛋白活性会降低细胞生长甚至化学抗性。最近，我们已经证明，由环状九肽组成的合成Id-蛋白质配体（1 Y）在浓度≥ 100 μ M时，可以将两种乳腺癌细胞系MCF-7和T47 D以及膀胱癌细胞T24的存活率降低至约50%。此外，环肽显示对MCF-7细胞的促凋亡和抗增殖作用。在此，我们表明，环肽不诱导细胞死亡的剂量为5 μ M，但它仍然抑制MCF-7和T24细胞增殖，这与细胞周期调节因子p27（Kip 1）的蛋白质水平增加。此外，1 Y-预处理的MCF-7，T47 D和T24细胞比未处理的细胞更容易受到三种光敏剂间四（羟基苯基）二氢卟酚，porfimer钠和金丝桃素的光毒性作用，这是应用于光动力疗法（PDT）。Id-蛋白质配体与每种光活化光敏剂的组合显示出对细胞活力降低的协同作用。总之，在浓度>= 100 μ M时具有中等癌细胞杀伤活性的Id-蛋白配体可以以低20倍且几乎没有毒性的剂量施用，以提高癌细胞对与光动力治疗相关的光毒性的敏感性。这表明在用于癌症治疗的组合药物方法中靶向Id蛋白的潜在益处。
The inhibitor of DNA binding and cell differentiation (Id) proteins are dominant negative regulators of the helix loop-helix transcription factor family and play a key role during development as well as in vascular disorders and cancer. In fact, impairing the Id-protein activity in cancer cells reduces cell growth and even chemoresistance. Recently, we have shown that a synthetic Id-protein ligand (1Y) consisting of a cyclic nonapeptide can reduce the viability of the two breast cancer cell lines MCF-7 and T47D and of the bladder cancer cells T24 to about 50% at concentrations >= 100 mu M. Moreover, the cyclopeptide displays both proapoptotic and antiproliferative effects on MCF-7 cells. Herein, we show that the cyclopeptide does not induce cell death at the dose of 5 mu M, but it still inhibits MCF-7 and T24 cell proliferation, which correlates with an increased protein level of the cell-cycle regulator p27(Kip1). Furthermore, 1Y-pretreated MCF-7, T47D, and T24 cells are more susceptible than untreated cells to the phototoxic effects of the three photosensitizers meta-tetra(hydroxyphenyl)chlorin, porfimer sodium, and hypericin, which are applied in photodynamic therapy (PDT). The combination of the Id-protein ligand with each of the light-activated photosensitizers shows synergistic effects on the reduction of cell viability. In conclusion, an Id-protein ligand with moderate cancer cell killing activity at concentrations >= 100 mu M can be applied at a 20-fold lower and barely toxic dose to raise the sensitivity of cancer cells towards phototoxicity associated with photodynamic treatment. This suggests the potential benefit of targeting the Id proteins in combined drug approaches for cancer therapy.