Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells
| Autor: | Ali Haydar Acikelli, David Diaz-Carballo, Sebastian Gustmann, Gunter Wennemuth, Raphael Stoll, Walter Bardenheuer, Holger Jastrow, Martin Feigel, Thorsten Kedziorski, Philip Dammann, Sascha Malak, Dirk Strumberg, Mhd. Ali Nazif |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Oncology
medicine.medical_specialty Magnetic Resonance Spectroscopy Cell Survival Medizin Mice Nude Antineoplastic Agents Biology Mass Spectrometry Propolis Cell Line Inhibitory Concentration 50 Mice Neuroblastoma Structure-Activity Relationship Cancer stem cell Internal medicine Drug Discovery medicine Cytotoxic T cell Animals Humans Pharmacology (medical) Cytotoxicity Chromatography High Pressure Liquid Cell Proliferation Pharmacology Chromatography Reverse-Phase Dose-Response Relationship Drug Molecular Structure Drug discovery Cancer medicine.disease Xenograft Model Antitumor Assays Multiple drug resistance Cell culture Drug Resistance Neoplasm Cancer research Neoplastic Stem Cells Female |
| Zdroj: | International journal of clinical pharmacology and therapeutics. 52(9) |
| ISSN: | 0946-1965 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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