Díaz-Carballo David, Acikelli Ali Haydar, Bardenheuer Walter, Gustmann Sebastian, Malak Sascha, Stoll Raphael, Kedziorski Thorsten, Nazif Mhd Ali, Jastrow Holger, Wennemuth Gunter, Dammann Philip, Feigel Martin, Strumberg Dirk
Int J Clin Pharmacol Ther. 2014 Sep;52(9):787-801. doi: 10.5414/CP202154.
Relapse of cancer months or years after an apparently successful therapy is probably caused by cancer stem cells (CSCs) due to their intrinsic features like dormant periods, radiorefraction, and acquired multidrug resistance (MDR) phenotypes, among other mechanisms of cellular drug evasiveness. Thus, the lack of currently efficacious interventions remains a major problem in the treatment of malignancies, together with the inability of existing drugs to destroy specifically CSCs. Neuroblastomas per se are highly chemotherapy-refractory extracranial tumors in infants with very low survival rates. So far, no effective cytostatics against this kind of tumors are clinically available. Therefore, we have put much effort into the development of agents to efficiently combat this malignancy. For this purpose, we tested several compounds isolated from Cuban propolis on induced CSCs (iCSC) derived from LAN-1 neuroblastoma cells which expressed several characteristics of tumor-initiating cells both in in-vitro and in-vivo models. Some small molecules such as flavonoids and polycyclic polyprenylated acylphloroglucinols (PPAP) were isolated using successive RT-HPLC cycles and identified employing mass spectrometry and NMR spectroscopic techniques. Their cytotoxicity was first screened in sensitive cell systems by MTT proliferation assays and afterwards studied in less sensitive neuroblastoma iCSC models. We found several compounds with considerable anti-iCSC activity, most of them belonging to the PPAP class. The majority of the compounds act in a pleiotropic manner on the molecular biology of tumors although their specific targets remain unclear. Nevertheless, two substances, one of them a flavonoid, induced a strong disruption of tubulin polymerization. In addition, an unknown compound strongly inhibited replicative enzymes like toposimerases I/II and DNA polymerase. Here, we report for the first time cytotoxic activities of small molecules isolated from Caribbean propolis which could be promising therapeutics or lead structures against therapy-refractory neuroblastoma entities. *Contributed equally.
在看似成功的治疗数月或数年之后癌症复发，可能是由癌症干细胞（CSCs）引起的，这归因于其内在特性，如休眠期、放射抵抗以及获得性多药耐药（MDR）表型等细胞逃避药物作用的机制。因此，目前缺乏有效的干预措施仍然是恶性肿瘤治疗中的一个主要问题，同时现有药物无法特异性地摧毁癌症干细胞。神经母细胞瘤本身是婴儿期极具化疗抵抗性的颅外肿瘤，生存率极低。到目前为止，临床上尚无针对这类肿瘤的有效细胞抑制剂。因此，我们投入了大量精力来开发有效对抗这种恶性肿瘤的药物。为此，我们测试了从古巴蜂胶中分离出的几种化合物对源自LAN - 1神经母细胞瘤细胞的诱导癌症干细胞（iCSC）的作用，这些诱导癌症干细胞在体外和体内模型中均表现出肿瘤起始细胞的若干特征。通过连续的反相高效液相色谱（RT - HPLC）循环分离出了一些小分子，如黄酮类化合物和多环多异戊烯基酰基间苯三酚（PPAP），并采用质谱和核磁共振光谱技术进行鉴定。首先通过MTT增殖试验在敏感细胞系统中筛选它们的细胞毒性，随后在敏感性较低的神经母细胞瘤iCSC模型中进行研究。我们发现了几种具有显著抗iCSC活性的化合物，其中大多数属于PPAP类别。尽管这些化合物的具体靶点尚不清楚，但大多数化合物对肿瘤分子生物学具有多效性作用。然而，有两种物质，其中一种是黄酮类化合物，可强烈破坏微管蛋白聚合。此外，一种未知化合物强烈抑制诸如拓扑异构酶I/II和DNA聚合酶等复制酶。在此，我们首次报道了从加勒比蜂胶中分离出的小分子的细胞毒性活性，这些小分子有望成为治疗难治性神经母细胞瘤实体的治疗药物或先导结构。*共同贡献。
