Mitochondrial toxicity of 2,5-diaziridinyl-3,6-bis-(carboethoxyamino)-1,4-benzoquinone

Abstract

2,5-Diaziridinyl-3,6-bis-(carboethoxyamino)-1,4-benzoquinone (AZQ) is an antitumor agent characterized by lipid solubility and the ability to penetrate the central nervous system. Two human glioma-derived cell lines, SNB-1 and SNB-2, proved by microcytotoxicity assay to be sensitive to AZQ, were examined with transmission electron microscopy for morphologic changes induced by this drug. AZQ was used in two ways: a) dissolved with dimethylacetamide (aqueous) at concentrations of 25 and 50 micrograms/ml and b) solid (surface plated) at 3.1 and 6.2 micrograms/mm2. A time study from 30 minutes to 48 hours was performed. Selective mitochondrial destruction was noted after 8 hours of exposure to AZQ. After 12 hours, condensation of chromatin along the periphery of the nucleus and dilation of endoplasmic reticulum were two other cellular reactions observed. Thus in addition to the known alkylating activity of AZQ, it has significant mitochondrial toxicity. This antimitochondrial effect is possibly an important factor in the antiglioma cell cytotoxicity of AZQ.