Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma.
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 < or =10 microM concentration. More interestingly, 17 compounds are active at < or =1 microM 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, eleven compounds are not currently used to treat NB. Among them, nine are FDA approved compounds, and three agents are undergoing clinical trials for various malignancies. Furthermore, we identified four 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.
Gheeya
Jinesh S
JS
Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD, USA.
Chen
Qing-Rong
QR
Benjamin
Christopher D
CD
Cheuk
Adam T
AT
Tsang
Patricia
P
Chung
Joon-Yong
JY
Metaferia
Belhu B
BB
Badgett
Thomas C
TC
Johansson
Peter
P
Wei
Jun S
JS
Hewitt
Stephen M
SM
Khan
Javed
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy*; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology
D000970:Antineoplastic Agents; D014315:Triterpenes; D020169:Caspases; C038106:cucurbitacin I