CXC195 exhibits strong protective effects against neuronal apoptosis by exerting
antioxidant activity. However, the pharmacological function of
CXC195 in
cancer remains to be elucidated. The present study demonstrated that
CXC195 exhibited significant cytotoxic effects, and induced cell cycle arrest and apoptosis in HepG2 human
hepatocellular carcinoma (HCC) cell lines. Following treatment of HepG2 cells with 150 µΜ
CXC195 for 24 , cell viability and the apoptotic rate were assessed using an MTT assay and Annexin V/
propidium iodide staining followed by flow cytometric analysis. Molecular markers of the cell cycle, apoptosis, mitochondrial function and endoplasmic reticulum (ER) stress were analyzed by western blot or polymerase chain reaction analysis.
Caspase activation, cytochrome c and apoptosis‑inducing factor release, and analysis of the B cell lymphoma 2 (Bcl‑2)‑associated X
protein/Bcl‑2 ratio demonstrated that the anticancer effects of
CXC195 in HepG2 cells were mediated by
caspase and mitochondria‑dependent apoptosis.
CXC195 also induced the expression of ER stress‑associated
proteins, including CCAAT‑enhancer‑binding
protein homologous
protein, and glucose‑regulated proteins 94 and 78, and led to the activation of multiple branches of ER stress transducers, including inositol‑requiring enzyme 1α‑apoptosis signal‑regulating kinase‑p38/c‑Jun N‑terminal
kinase, and
protein kinase R‑like endoplasmic reticulum kinase‑eukaryotic translation initiation factor 2α‑activating
transcription factor (ATF)4 and ATF6, in the HepG2 cells. In addition,
CXC195 inhibited the phosphorylation of
phosphoinositide 3‑kinase (PI3K), Akt and
mammalian target of rapamycin (mTOR) in the HepG2 cells. These effects were enhanced following treatment with selected inhibitors of PI3K (
LY294002), Akt (SH‑6) and mTOR (
rapamycin). Furthermore, these inhibitors enhanced the pro‑apoptotic effects of
CXC195 in the HepG2 cells. In conclusion, the results of the present study indicated that
CXC195 induced apoptosis and ER stress in HepG2 cells through the inhibition of the PI3K/Akt/mTOR signaling pathway.