Neuroblastoma (NB), the most common extracranial solid tumor of childhood, derives from neural crest cells of the peripheral sympathetic nervous system. Despite advances in cancer chemotherapy, as much as 50% of NB patients diagnosed with the high-risk form of the disease will be refractory to treatment or experience relapse after treatment [1]. In preliminary studies, three dichloromethane-soluble extracts of Juniperus oblonga M. Bieb. (Cupressaceae) not only inhibited proliferation of NB cells in culture, but also increased intracellular calcium in them [2]. The compounds responsible for the inhibition of NB in cell culture in Juniperus species have not been previously reported.
In the present study, a bioactivity guided fractionation was performed on the three active extracts, followed by structure determination based largely on LC-MS and NMR data. Twenty-six compounds have been identified, including lignans, coumarins, biflavones and diterpenes. Some of these compounds inhibit NB cell viability (with or without MYCN amplification) by altering cell cycle progression and inducing apoptosis. Additionally, these compounds show similar activity in drug resistant and drug sensitive NB. This may be clinically significant as there are currently no effective treatments for drug resistant NB. Therefore, some of the juniper compounds may represent leads toward an effective treatment for NB, particularly high risk, MYCN amplified, and drug resistant forms.
In light of the limited nature of this sample, additional Juniperus species from the Chinese flora have been obtained and evaluated against NB in cell culture leading to the discovery of additional compounds with chemically distinct properties.
[1]. Cole, K.A., and Maris, J.M. (2012) Clinical Cancer Research 18(9), 2423-2428.
[2]. Lange, I., Moschny, J., Kerimov, V., Khutsishvili, M., Atha, D.E., Borris, R.P., and Koomoa-Lange, D.-L. (2015) J. Pharm. Pharm. Scien. 1(1) 1-7.