Effect of indole ethyl isothiocyanates on proliferation, apoptosis, and MAPK signaling in neuroblastoma cell lines

Several indole ethyl isothiocyanate (IEITC) analogs were designed, synthesized, and screened to evaluate their cytotoxicity against neuroblastoma (NB) cells in-vitro. In NB, predominantly a tumor of early childhood, survival remains low despite aggressive treatments. Therefore, novel treatment strategies are greatly needed. The objective of the present study was to study the therapeutic potential of IEITC by analyzing the cytotoxic, anti-proliferative, and apoptotic effects on NB cell lines. 7-Methyl-indole-3-ethyl isothiocyanate (7Me-IEITC) proved to be cytotoxic to various NB cell lines (SMS-KCNR, SK-N-SH, SH-SY5Y, and IMR-32) with an IC50 at 2.5–5.0 μM, while primary control cells (lung fibroblasts) were not affected. 7Me-IEITC led to the activation of apoptotic markers caspase-3, -8, and -9, caused activation of pro-apoptotic p38 MAPK and SAP/JNK, and down-regulated pro-survival factor AKT in SMS-KCNR cells. Moreover, 7Me-IEITC displayed anti-proliferative effects (IC50 at 600 nM) and caused an arrest in cell cycle progression. This wide effect of 7Me-IEITC on NB cell signaling and survival suggests that it could be developed as a therapeutic agent against neuroblastoma.

Graphical abstractSeveral indole ethyl isothiocyanate (IEITC) analogs were designed, synthesized, and screened in viability assays against neuroblastoma (NB) cells in vitro. The cytotoxicity of IEITC with non-polar groups such as –Me and –Benzyloxy (BzO) was significantly higher than that of synthesized IEITC with polar groups such as –OH and –OMe. Substitution at the 5- and 7-position (2d and 2g) resulted in an additional improvement. 7Me-IEITC (2g) inhibited NB viability and proliferation along with caspase activation, inactivation of survival marker Akt, and activation of pro-apoptotic MAPKs.Figure optionsDownload full-size imageDownload as PowerPoint slide