Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.

• Keywords
• DpC, EGFR, MYC, NDRG1, lipid droplet, neuroblastoma, thiosemicarbazone,
• MeSH
• Gene Amplification drug effects   MeSH
• Models, Biological MeSH
• Iron Chelating Agents pharmacology   MeSH
• Down-Regulation drug effects   MeSH
• ErbB Receptors metabolism   MeSH
• Phosphorylation drug effects   MeSH
• Stress, Physiological drug effects   MeSH
• Intracellular Signaling Peptides and Proteins metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Neuroblastoma metabolism   pathology   MeSH
• Cell Cycle Proteins metabolism   MeSH
• N-Myc Proto-Oncogene Protein metabolism   MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Pyridines pharmacology   MeSH
• Signal Transduction * MeSH
• Thiosemicarbazones pharmacology   MeSH
• Cell Shape drug effects   MeSH
• Gene Silencing drug effects   MeSH
• Up-Regulation drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Iron Chelating Agents MeSH
• di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone MeSH Browser
• ErbB Receptors MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• N-myc downstream-regulated gene 1 protein MeSH Browser
• Cell Cycle Proteins MeSH
• N-Myc Proto-Oncogene Protein MeSH
• Proto-Oncogene Proteins c-akt MeSH
• Pyridines MeSH
• Thiosemicarbazones MeSH

Sobuzoxane (MST-16) is an approved anticancer agent, a pro-drug of bisdioxopiperazine analog ICRF-154. Due to the structural similarity of ICRF-154 to dexrazoxane (ICRF-187), MST-16 deserves attention as a cardioprotective drug. This study presents for the first time UHPLC-MS/MS assay of MST-16, ICRF-154 and its metabolite (EDTA-diamide) in cell culture medium, buffer, plasma and cardiac cells and provides data on MST-16 bioactivation under conditions relevant to investigation of cardioprotection of this drug. The analysis of these compounds that differ considerably in their lipophilicity was achieved on the Zorbax SB-Aq column using a mixture of aqueous ammonium formate and methanol as a mobile phase. The biological samples were either diluted or precipitated with methanol, which was followed by acidification for the assay of MST-16. The method was validated for determination of all compounds in the biological materials. The application of the method for analysis of samples from in vitro experiments provided important findings, namely, that (1) MST-16 is quickly decomposed in biological environments, (2) the cardiac cells actively metabolize MST-16, and (3) MST-16 readily penetrates into the cardiac cells and is converted into ICRF-154 and EDTA-diamide. These data are useful for the in-depth examination of the cardioprotective potential of this drug.

• MeSH
• Edetic Acid chemistry   MeSH
• Myocytes, Cardiac cytology   metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Piperazines analysis   MeSH
• Rats, Wistar MeSH
• Antineoplastic Agents analysis   metabolism   MeSH
• Razoxane analogs & derivatives   chemistry   metabolism   MeSH
• Tandem Mass Spectrometry MeSH
• Chromatography, High Pressure Liquid MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,2-bis(3,5-dioxopiperazin-1-yl)ethane MeSH Browser
• Edetic Acid MeSH
• Piperazines MeSH
• Antineoplastic Agents MeSH
• Razoxane MeSH
• sobuzoxane MeSH Browser