Inhibition of Akt kinase increases cytotoxicity of metaiodobenzylguanidine to neuroblastoma cells

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Year of publication 2015
Type Appeared in Conference without Proceedings
MU Faculty or unit

Faculty of Science

Description Neuroblastoma is a malignant neuroendocrine tumor, arising from the sympathetic nervous system. It is the most common extracranial solid cancer in childhood. Meta-iodobenzylguanidine (MIBG) and its radioactive form 131I-MIBG are functional analogues of the neurotransmitter norepinephrine that are taken up by 90 to 95% of all neuroblastomas. Whereas most tissues accumulate MIBG by a nonspecific process, cells of the neuroadrenergic tissues and their malignant derivatives exhibit active uptake of the tracer that is mediated by the norepinephrine transporter. Although MIBG is selectively taken up and stored by tumours derived from the neural crest and might stress them in several ways (lipidperoxidation, inhibition of mitochondrial respiration), its toxicity is not very high. Thus, the goal of this study is to increase cytotoxicity of MIBG to neuroblastoma cells. We found that Akt 1/2 kinase inhibitor synergistically increases cytotoxicity of MIBG to neuroblastoma SK-N-Be(2) and SH-SY5Y cells as assessed by combination index analysis. Similar results were obtained for combination of MIBG with L- Buthionine-sulfoximine (BSO), an inhibitor of glutathione synthesis. Cytotoxicity of the MIBG/BSO combination depends on ROS production and diminishes in hypoxia (1% O2). Nevertheless, cytotoxicity of MIBG in combination with Akt1/2 kinase inhibitor is not ROS dependent and is preserved in hypoxic culture conditions. Thus, inhibition of the Akt kinase might be a promising strategy to increase cytotoxicity of MIBG to neuroblastoma.
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