Wang Shan, Willenberg Ina, Krohn Michael, Hecker Tanja, Meckelmann Sven, Li Chang, Pan Yuanjiang, Schebb Nils Helge, Steinberg Pablo, Empl Michael Telamon
Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
Institute of Food Chemistry, University of Wuppertal, Wuppertal, Germany.
PLoS One. 2017 Jan 23;12(1):e0170502. doi: 10.1371/journal.pone.0170502. eCollection 2017.
Although resveratrol exerts manifold antitumorigenic effects in vitro, its efficacy against malignancies in vivo seems limited. This has been increasingly recognized in recent years and has prompted scientists to search for structurally related compounds with more promising anticarcinogenic and/or pharmacokinetic properties. A class of structurally modified resveratrol derivatives, so-called resveratrol imine analogs (IRA's), might meet these requirements. Therefore, the biological activity of five of these compounds was examined and compared to that of resveratrol. Firstly, the antiproliferative potency of all five IRA's was investigated using the p53 wildtype-carrying colorectal carcinoma cell line HCT-116wt. Then, using the former and a panel of various other tumor cell lines (including the p53 knockout variant HCT-116p53-/-), the growth-inhibiting and cell cycle-disturbing effects of the most potent IRA (IRA 5, 2-[[(2-hydroxyphenyl)methylene]amino]-phenol) were studied as was its influence on cyclooxygenase-2 expression and activity. Finally, rat liver microsomes were used to determine the metabolic stability of that compound. IRA 5 was clearly the most potent compound in HCT-116wt cells, with an unusually high IC50-value of 0.6 μM. However, in the other five cell lines used, the antiproliferative activity was mostly similar to resveratrol and the effects on the cell cycle were heterogeneous. Although all cell lines were affected by treatment with IRA 5, cells expressing functional p53 seemed to react more sensitively, suggesting that this protein plays a modulating role in the induction of IRA 5-mediated biological effects. Lastly, IRA 5 led to contradictory effects on cyclooxygenase-2 expression and activity and was less glucuronidated than resveratrol. As IRA 5 is approximately 50 times more toxic towards HCT-116wt cells, exerts different effects on the cyclooxygenase-2 and is metabolized to a lesser extent, it shows certain advantages over resveratrol and could therefore serve as basis for additional chemical modifications, potentially yielding compounds with more favorable biological and pharmacokinetic features.
尽管白藜芦醇在体外具有多种抗肿瘤作用，但其对体内恶性肿瘤的疗效似乎有限。近年来，这一点已得到越来越多的认可，并促使科学家们寻找具有更有前景的抗癌和/或药代动力学特性的结构相关化合物。一类结构修饰的白藜芦醇衍生物，即所谓的白藜芦醇亚胺类似物（IRA's），可能符合这些要求。因此，研究了其中五种化合物的生物活性，并与白藜芦醇进行了比较。首先，使用携带p53野生型的结肠癌细胞系HCT-116wt研究了所有五种IRA's的抗增殖能力。然后，使用前者和一组其他各种肿瘤细胞系（包括p53基因敲除变体HCT-116p53-/-），研究了最有效的IRA（IRA 5，2-[[(2-羟基苯基)亚甲基]氨基]-苯酚）的生长抑制和细胞周期干扰作用，以及其对环氧合酶-2表达和活性的影响。最后，使用大鼠肝微粒体来确定该化合物的代谢稳定性。IRA 5显然是HCT-116wt细胞中最有效的化合物，其IC50值异常高，为0.6μM。然而，在使用的其他五种细胞系中，抗增殖活性大多与白藜芦醇相似，对细胞周期的影响也各不相同。尽管所有细胞系都受到IRA 5处理的影响，但表达功能性p53的细胞似乎反应更敏感，这表明该蛋白在IRA 5介导的生物学效应的诱导中起调节作用。最后，IRA 5对环氧合酶-2的表达和活性产生了矛盾的影响，并且比白藜芦醇更少地进行葡萄糖醛酸化。由于IRA 5对HCT-116wt细胞的毒性大约高50倍，对环氧合酶-2产生不同的影响，并且代谢程度较低，它显示出优于白藜芦醇的某些优势，因此可以作为进一步化学修饰的基础，可能产生具有更有利的生物学和药代动力学特征的化合物。
