Adapalene potentiates the cytotoxicity of anti-cancer drugs by enhancing cell cycle dysregulation and apoptosis in MKN-45 cells

Adapalene is a third-generation synthetic retinoid that has been approved by the FDA as a dermatological drug was recently repurposed for its potential anti-cancer effects. Here, its anti-cancer potential was determined in human gastric adenocarcinoma cell lines. Adapalene did not show significant cytotoxicity toward AGS and MKN-45 cells, but displayed synergistic or additive effects in inhibiting cell growth and increasing apoptosis in MKN-45 cells, but not AGS cells, when combined with 5-FU, cisplatin, docetaxel, or doxorubicin. Co-treatment with adapalene plus docetaxel or doxorubicin increased DNA damage and S-phase arrest without affecting the expression levels of HR23A/B, XPC, or Rad51. In MKN-45 cells exposed to docetaxel or doxorubicin, adapalene co-treatment downregulated Aurora A and upregulated p21, potentially contributing to its ability to enhance DNA damage and cell cycle dysregulation, and increased reactive oxygen species (ROS) accumulation, which may potentiate the cytotoxicity of the anti-cancer agents. Our present results reveal that adapalene is not cytotoxic towards MKN-45 gastric cancer cells when applied alone, but can synergistically enhance the sensitivity of these cells to conventional chemotherapeutic drugs. Further investigations are warranted to fully elucidate the mechanisms underlying the synergistic effects of adapalene and identify markers that could, given the heterogeneity of gastric cancers, identify patients who are likely to benefit from adapalene co-treatment.