Journal
ANTICANCER RESEARCH
Volume 41, Issue 3, Pages 1171-1181Publisher
INT INST ANTICANCER RESEARCH
DOI: 10.21873/anticanres.14874
Keywords
Drug resistance; C282Y HFE; HSP27-Akt-JNK activation; in vivo tumor model; neuroblastoma; thiobarbituric acid
Categories
Funding
- National Cancer Institute [R21CA167406]
- Four Diamonds Fund Research Program [PennStateHealth Children's Hospital] [417-20HY 43BX]
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CC-I exhibits potent cytotoxicity on therapy-resistant neuroblastoma cells but limited cytotoxicity on human primary dermal fibroblast cells. It shows robust anti-tumor effects in in vivo mouse tumor models, possibly through HSP27-Akt-JNK activation.
Background/Aim: We have previously reported the identification of the cytotoxic chemotype compound-I (CC-I) from a chemical library screening against glioblastoma. Materials and Methods: The biological activity of CC-I on drug-resistant neuroblastomas [e.g., HFE gene variant C282Y stably transfected human neuroblastoma SHSY5Y cells (C282Y HFE/SH-SY5Y), SK-N-AS] was characterized using cell culture models and in vivo mouse tumor models. Results: CC-I had potent cytotoxicity on therapy-resistant neuroblastoma cells and limited cytotoxicity on human primary dermal fibroblast cells. In addition, CC-I showed a robust anti-tumor effect on therapy resistant human neuroblastoma C282Y HFE/SH-SY5Y cells but not on SK-N-AS cells in a subcutaneous tumor model. CC-I induced phosphorylation of heat shock protein 27 (HSP27), protein kinase B (Akt), and c-Jun N-terminal kinase (JNK) in C282Y HFE/SH-SY5Y neuroblastoma cells. Conclusion: CC-I may be an effective therapeutic option for therapy-resistant neuroblastomas, especially if they express the C282Y HFE gene variant. Its anti-tumor effects are possibly through HSP27-Akt-JNK activation.
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