O2/3 exposure inhibits cell progression affecting cyclin B1/cdk 1 activity in SK-N-SH while induces apoptosis in SK-N-DZ neuroblastoma cells

In search for innovative therapeutic agents for children neuroblastoma, the oxygen therapy could be considered an alternative antitumoral treatment. Given the physiochemical properties ofO2/3 gas mixture including fairly low aqueous solubility and spreading, and the interesting perspective of hyperoxia, we analyzed the inhibitory effect ofO2/3 treatment on two human neuroblastoma cell lines (SK-N-SH and SK-N-DZ). In this study, we demonstrated thatO2/3 treatment was able to induce cell growth inhibition and cell cycle perturbation in both cell lines. We observed an arrest at G2 phase, accompanied by an alteration in the expression and localization of cyclin B1/cdk1 complex and a reduction in its activity in SK-N-SH cells. This reduction was consistent with the increase in both Wee1 and chk1 protein levels. On the contrary, O2/3 induced apoptosis in SK-N-DZ cells via caspase 3 activation and Poly ADP-ribose polymerase-1 (PARP) cleavage, associated with an increase in the pro-apoptotic Bax protein. Consequently, we considered the possibility of improving the responsiveness to chemotherapeutic agents such as Cisplatin, Etoposide, and Gemcitabine in combination with O2/3 treatment. The combined treatments produced a stronger cell inhibitory effect than Cisplatin and Etoposide used alone in SK-N-SH cells.Onthe contrary, the combination data were not significantly different from O2/3 treatment alone in SK-N-DZ cells, thus suggesting that the obtained changes in cell growth inhibition were due to the effect of O2/3 alone.