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.