Abstract
BackgroundGlioma has one of the highest mortality rates of all tumors of the nervous system and commonly used treatments almost always fail to achieve tumor control. Low-dose carbon-ion radiation can effectively target cancer and tumor cells, but the mechanisms of growth inhibition induced by heavy-ion radiation via the PI3K/Akt signaling pathway are unknown, and inhibition by heavy-ion radiation is minor in C6 cells.MethodsCarbon-ion radiation was used to investigate the effects of heavy-ion radiation on C6 cells, and suppression of Akt was performed using perifosine. MTT assays were used to investigate optimal perifosine treatment concentrations. Clone formation assays were used to investigate the growth inhibition effects of carbon-ion radiation and the effects of radiation with Akt inhibition. Lactate dehydrogenase release, superoxide dismutase activity, and malondialdehyde content were assessed to investigate oxidative stress levels. Expression levels of proteins in the PI3K/Akt/p53 signaling pathway were assessed via western blotting.ResultsThe 10% maximum inhibitory concentration of perifosine was 19.95 μM. In clone formation assays there was no significant inhibition of cell growth after treatment with heavy-ion irradiation, whereas perifosine enhanced inhibition. Heavy-ion radiation induced lactate dehydrogenase release, increased the level of malondialdehyde, and reduced superoxide dismutase activity. Akt inhibition promoted these processes. Heavy-ion radiation treatment downregulated Akt expression, and upregulated B-cell lymphoma-2 (Bcl-2) expression. p53 and Bcl-2 expression were significantly upregulated, and Bcl-2-associated X protein (Bax) expression was downregulated. The expression profiles of pAkt, Bcl-2, and Bax were reversed by perifosine treatment. Caspase 3 expression was upregulated in all radiation groups.ConclusionsThe growth inhibition effects of low-dose heavy-ion irradiation were not substantial in C6 cells, and Akt inhibition induced by perifosine enhanced the growth inhibition effects via proliferation inhibition, apoptosis, and oxidative stress. Akt inhibition enhanced the effects of heavy-ion radiation, and the PI3K/Akt/p53 signaling pathway may be a critical component involved in the process.
Highlights
Glioma is a neurogliocytic tumor that originates in the brain or spine, and it is one of the most common and deadly tumors of the nervous system [1,2,3,4]
Growth Inhibition Induced by Heavy-Ion Radiation, and Effects of Akt Inhibition
Cell growth inhibition was measured via the MTT assay, to determine the optimal treatment concentration of perifosine
Summary
Glioma is a neurogliocytic tumor that originates in the brain or spine, and it is one of the most common and deadly tumors of the nervous system [1,2,3,4]. Because of glioma’s high tendency to invade surrounding tissues commonly used treatment protocols seldom result in tumor control [6]. Radiation therapy is a relatively standard cancer treatment, and it is generally used to diminish the volume of the neoplasm and increase the effective killing of cancer cells. Carbon-ion radiation has numerous effects on cells by breaking chemical bonds in all basic cellular components such as DNA, and 12C6+ ions generate high relative biological efficiency and steep lateral dose gradients between the target tissues and surrounding areas by reducing lateral scattering [11,12,13,14]. Despite the fact that heavy-ion radiotherapy has a greater capacity to target cancer and is associated with less injury to the surrounding normal tissues, the mechanisms involved in the growth inhibition effects are unknown. Lowdose carbon-ion radiation can effectively target cancer and tumor cells, but the mechanisms of growth inhibition induced by heavy-ion radiation via the PI3K/Akt signaling pathway are unknown, and inhibition by heavy-ion radiation is minor in C6 cells
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