Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia.
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia.
Eur J Med Chem. 2017 Sep 8;137:558-574. doi: 10.1016/j.ejmech.2017.05.063. Epub 2017 Jun 3.
Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal and show increased resistance to chemo- and radiotherapy. Targeting CSC, rather than cancer cells in general, is a novel and promising strategy for cancer treatment. Novel therapeutic approaches, such as photodynamic therapy (PDT) have been investigated. A promising group of phototherapeutic agents are reactive intermediates - quinone methides (QMs). This study describes preparation of QM precursor, 2-hydroxy-3-hydroxymethylanthracene (2) and a detailed photochemical and photobiological investigation on similar anthracene derivatives 3 and 4. Upon photoexcitation with near visible light at λ > 400 nm 1 and 2 give QMs, that were detected by laser flash photolysis and their reactivity with nucleophiles has been demonstrated in the preparative irradiation experiments where the corresponding adducts were isolated and characterized. 3 and 4 cannot undergo photodehydration and deliver QM, but lead to the formation of phenoxyl radical and singlet oxygen, respectively. The activity of 1-4 was tested on a panel of human tumor cell lines, while special attention was devoted to demonstrate their potential selectivity towards the cells with CSC-like properties (HMLEshEcad). Upon the irradiation of cell lines treated with 1-4, an enhancement of antiproliferative activity was demonstrated, but the DNA was not the target molecule. Confocal microscopy revealed that these compounds entered the cell and, upon irradiation, reacted with cellular membranes. Our experiments demonstrated moderate selectivity of 2 and 4 towards CSC-like cells, while necrosis was shown to be a dominant cell death mechanism. Especially interesting was the selectivity of 4 that produced higher levels of ROS in CSC-like cells, which forms the basis for further research on cancer phototherapy, as well as for the elucidation of the underlying mechanism of the observed CSC selectivity based on oxidative stress activation.
癌症干细胞（CSC）是一类具有胚胎干细胞多能性和自我更新能力的肿瘤细胞亚群，对化疗和放疗具有更高的抵抗力。靶向 CSC 而不是一般的癌细胞是一种新的、有前途的癌症治疗策略。新的治疗方法，如光动力疗法（PDT）已经被研究过。一组有前途的光疗药物是反应性中间体 - 醌甲醚（QM）。本研究描述了 QM 前体 2-羟基-3-羟甲基蒽（2）的制备，并对类似蒽衍生物 3 和 4 进行了详细的光化学和光生物学研究。在近可见波长（λ>400nm）下光激发 1 和 2 会产生 QM，可以通过激光闪光光解检测到，并在制备辐照实验中证明了它们与亲核试剂的反应性，其中分离并表征了相应的加合物。3 和 4 不能经历光脱水并提供 QM，但分别导致酚氧自由基和单线态氧的形成。测试了 1-4 对一系列人类肿瘤细胞系的活性，特别关注证明它们对具有 CSC 样特性的细胞（HMLEshEcad）的潜在选择性。在用 1-4 处理的细胞系照射后，证明了抗增殖活性增强，但 DNA 不是靶分子。共聚焦显微镜显示这些化合物进入细胞，在照射后与细胞膜反应。我们的实验证明了 2 和 4 对 CSC 样细胞的中等选择性，而坏死被证明是一种主要的细胞死亡机制。特别有趣的是 4 的选择性，它在 CSC 样细胞中产生更高水平的 ROS，这为进一步研究癌症光疗以及阐明基于氧化应激激活的观察到的 CSC 选择性的潜在机制奠定了基础。
