Abstract
BackgroundNeuroblastoma is a relatively common and highly belligerent childhood tumor with poor prognosis by current therapeutic approaches. A novel anti-cancer agent of the di-2-pyridylketone thiosemicarbazone series, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), demonstrates promising anti-tumor activity. Recently, a second-generation analogue, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), has entered multi-center clinical trials for the treatment of advanced and resistant tumors. The current aim was to examine if these novel agents were effective against aggressive neuroblastoma in vitro and in vivo and to assess their mechanism of action.MethodsNeuroblastoma cancer cells as well as immortalized normal cells were used to assess the efficacy and selectivity of DpC in vitro. An orthotopic SK-N-LP/Luciferase xenograft model was used in nude mice to assess the efficacy of DpC in vivo. Apoptosis in tumors was confirmed by Annexin V/PI flow cytometry and H&E staining.ResultsDpC demonstrated more potent cytotoxicity than Dp44mT against neuroblastoma cells in a dose- and time-dependent manner. DpC significantly increased levels of phosphorylated JNK, neuroglobin, cytoglobin, and cleaved caspase 3 and 9, while decreasing IkBα levels in vitro. The contribution of JNK, NF-ĸB, and caspase signaling/activity to the anti-tumor activity of DpC was verified by selective inhibitors of these pathways. After 3 weeks of treatment, tumor growth in mice was significantly (p < 0.05) reduced by DpC (4 mg/kg/day) given intravenously and the agent was well tolerated. Xenograft tissues showed significantly higher expression of neuroglobin, cytoglobin, caspase 3, and tumor necrosis factor-α (TNFα) levels and a slight decrease in interleukin-10 (IL-10).ConclusionsDpC was found to be highly potent against neuroblastoma, demonstrating its potential as a novel therapeutic for this disease. The ability of DpC to increase TNFα in tumors could also promote the endogenous immune response to mediate enhanced cancer cell apoptosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0330-x) contains supplementary material, which is available to authorized users.
Highlights
Neuroblastoma is a relatively common and highly belligerent childhood tumor with poor prognosis by current therapeutic approaches
Due to its high efficacy and selectivity, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT; Fig. 1b) was chosen as the first lead di-2-pyridylketone thiosemicarbazone (DpT) analogue [7, 8] with its marked activity being confirmed by others [22,23,24]
The results demonstrate that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) shows marked and selective anti-tumor activity, which could be useful for the treatment of neuroblastoma
Summary
Neuroblastoma is a relatively common and highly belligerent childhood tumor with poor prognosis by current therapeutic approaches. Due to its high efficacy and selectivity, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT; Fig. 1b) was chosen as the first lead DpT analogue [7, 8] with its marked activity being confirmed by others [22,23,24] This agent has been demonstrated to upregulate the potent metastasis suppressor, N-myc downstream-regulated gene (NDRG1) [25], which inhibits the epithelial to mesenchymal transition [15] and results in suppression of oncogenic signaling, tumor cell migration [15,16,17,18,19,20,21], and metastasis in vivo [23]
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