Differential sensitivity of p44/p42-MAPK- and PI3K/Akt-targeted neuroblastoma subtypes to arsenic trioxide.

PI3K/Akt and MAPK/ERK pathways are differentially activated in neuroblastoma (NB) cell types. In an effort to enhance the effectiveness of the NB treatment, we designed experiments to evaluate the effects of ATO in combination with PI3K and MEK1/2 specific inhibitors, LY29004 and U0126, respectively, in SK-N-MC and SK-N-BE(2) cell lines. The results indicated that specific inhibition of PI3K and MEK1/2 significantly enhanced antiproliferative and proapoptotic effects of ATO in SK-N-BE(2), but not in SK-N-MC. Furthermore, in SK-N-BE(2), NF-κB activation was significantly suppressed by LY29004+ATO treatments as compared with ATO alone, indicating that inhibition of PI3K may enhance anti-neoplastic properties of ATO in I-type NB cells through suppression of NF-κB. Moreover, expressions of c-Myc, Bad, Bax and ATM in SK-N-BE(2) cell line were significantly increased by U0126+ATO treatment as compared to treatment with ATO alone. Expression of telomerase hTERT was almost depleted by U0126+ATO treatment. Regarding the fact that activation of PI3K and MAPK in SK-N-BE(2) is higher than in other NB subtypes, we hypothesize that growth of SK-N-BE(2) cell line is highly dependent on these pathways and inhibition of these pathways may has promise for the treatment of multi-drug resistant I-type NB cells by ATO. However, for successful strategies for the treatment of this heterogeneous tumor, other combinations approaches need to be considered to simultaneously target other NB cells.