Research Paper

Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma

Volume 8, Issue 24   December 15, 2009
Pages 2386 - 2395
http://dx.doi.org/10.4161/cbt.8.24.10184
Authors: Jinesh S. Gheeya, Qing-Rong Chen, Christopher D. Benjamin, Adam T. Cheuk, Patricia Tsang, Joon-Yong Chung, Belhu B. Metaferia, Thomas C. Badgett, Peter Johansson, Jun S. Wei, Stephen M. Hewitt and Javed Khan

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Abstract:
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active against NB cell lines at ≤ 10 μM concentration. More interestingly, 17 compounds are active at ≤ 1 μM concentration, and they act through a wide spectrum of diverse mechanisms such as mitotic inhibition, topoisomerase inhibition, targeting various biological pathways, and unknown mechanisms. The majority of these active compounds also induced caspase 3/7 by more than 2-fold. Of these 17 active compounds against NB cell lines at sub-micromolar concentration, 11 compounds are not currently used to treat NB. Among them, 9 are FDA approved compounds, and 3 agents are undergoing clinical trials for various malignancies. Furthermore, we identified 4 agents active against these NB cell lines that have not yet been tested in the clinical setting. Finally we demonstrated that Cucurbitacin I inhibits neuroblastoma cell growth through inhibition of STAT3 pathway. These drugs thus represent potential novel therapeutic agents for patients with NB, and further validation studies are needed to translate them to the clinic.

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