title: Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells.
abstract: 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.
authors.forename: David
authors.initials: D
authors.lastname: Díaz-Carballo
authors.forename: Ali Haydar
authors.initials: AH
authors.lastname: Acikelli
authors.forename: Walter
authors.initials: W
authors.lastname: Bardenheuer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gustmann
authors.forename: Sascha
authors.initials: S
authors.lastname: Malak
authors.forename: Raphael
authors.initials: R
authors.lastname: Stoll
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kedziorski
authors.forename: Mhd Ali
authors.initials: MA
authors.lastname: Nazif
authors.forename: Holger
authors.initials: H
authors.lastname: Jastrow
authors.forename: Gunter
authors.initials: G
authors.lastname: Wennemuth
authors.forename: Philip
authors.initials: P
authors.lastname: Dammann
authors.forename: Martin
authors.initials: M
authors.lastname: Feigel
authors.forename: Dirk
authors.initials: D
authors.lastname: Strumberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011429:Propolis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011429:Propolis