Effects of H 2 O 2 Treatment Combined With PI3K Inhibitor and MEK Inhibitor in AGS Cells: Oxidative Stress Outcomes in a Model of Gastric Cancer

• Published in: Frontiers in oncology Vol. 12; p. 860760
• Main Authors: Savino, Luca, Di Marcantonio, Maria Carmela, Moscatello, Carmelo, Cotellese, Roberto, Centurione, Lucia, Muraro, Raffaella, Aceto, Gitana Maria, Mincione, Gabriella
• Format: Journal Article
• Language: English
• Published: Switzerland 2022
• Subjects: PI3K and MAPK inhibitors; gastric cancer; reactive oxygen species; ErbB receptors; base excision repair system
• ISSN: 2234-943X; 2234-943X

Gastric cancer is worldwide the fifth and third cancer for incidence and mortality, respectively. Stomach wall is daily exposed to oxidative stress and BER system has a key role in the defense from oxidation-induced DNA damage, whilst ErbB receptors have important roles in the pathogenesis of cancer. We used AGS cells as an aggressive gastric carcinoma cell model, treated with H
O
alone or combined with ErbB signaling pathway inhibitors, to evaluate the effects of oxidative stress in gastric cancer, focusing on the modulation of ErbB signaling pathways and their eventual cross-talk with BER system. We showed that treatment with H
O
combined with PI3K/AKT and MEK inhibitors influenced cell morphology and resulted in a reduction of cancer cell viability. Migration ability was reduced after H
O
treatment alone or combined with MEK inhibitor and after PI3K/AKT inhibitor alone. Western blotting analysis showed that oxidative stress stimulated EGFR pathway favoring the MAPKs activation at the expense of PI3K/AKT pathway. Gene expression analysis by RT-qPCR showed
and
increase under oxidative stress conditions. Therefore, we suggest that in AGS cells a pro-oxidant treatment can reduce gastric cancer cell growth and migration
a different modulation of PI3K and MAPKs pathways. Moreover, the observed
and
induction is a cellular response to protect the cells from H
O
-induced cell death. In conclusion, to tailor specific combinations of therapies and to decide which strategy to use, administration of a chemotherapy that increases intracellular ROS to toxic levels, might not only be dependent on the tumor type, but also on the molecular targeting therapy used.