Selective Cytotoxic Effects of 5-Trifluoromethoxy-1H-indole-2,3-dione 3-Thiosemicarbazone Derivatives on...

The present study aims to identify the anticancer effect of novel 1H-indole-2,3-dione 3- thiosemicarbazone derivatives. These compounds could be promising anticancer agents in leukemia treatment.

Conventional chemotherapeutic agents accumulate in both normal and tumor cells due to nonspecificity. For effective cancer treatment, new drugs need to be developed to make chemotherapeutics selective for cancer cells. The ultimate goal of cancer treatment is to reduce systemic toxicity and improve the quality of life.

In this study, the anticancer effects of 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives (A-L) were investigated in chronic myelogenous leukemia K562, Burkitt's lymphoma P3HR1, acute promyelocytic leukemia HL60 cells, and vincristine-resistant sublines of K562 and P3HR1 cells. Additionally, the compounds were tested on lymphoid-derived cells from ALL patients. In order to investigate the particular mechanism of death caused by the cytotoxic effects of the compounds, immunohistochemical caspase 3 staining was performed in P3HR1 cells, and the resulting apoptotic activities were demonstrated.

All tested compounds have been found to have cytotoxic effects against lymphoma cells at submicromolar concentrations (IC₅₀= 0.89-1.80 μM). Most compounds show significant selectivity for the P3HR1 and P3HR1 Vin resistance. The most effective and selective compound is 4-bromophenyl substituted compound I (IC₅₀=0.96 and 0.89 μM). Cyclohexyl and benzyl substituted compounds D and E have also been found to have cytotoxic effects against K562 cell lines (IC₅₀=2.38 μM), while the allyl substituted compound C is effective on all cell lines (IC₅₀=1.13-2.21 μM). 4-Fluorophenyl substituted F compound has been observed to be effective on all cells (IC₅₀=1.00-2.41 μM) except K562 cell. Compound C is the only compound that shows inhibition of HL-60 cells (IC₅₀= 1.13 μM). Additionally, all compounds exhibited cytotoxic effects on lymphoidderived cells at 1μM concentration. These results are in accordance with the results obtained in lymphoma cells.

All compounds tested have submicromolar concentrations of cytotoxic effects on cells. These compounds hold potential for use in future treatments of leukemia.