Novel aloe emodin–hydroxyethyl piperazine hybrid dihydrochloride induces oral cancer CAL-27 cells apoptosis through ROS production, DNA damage and mitochondrial pathways

Oral cancer severely affects the quality of life of patients, and the primary treatment is surgery, due to a lack of specific drugs. Aloe emodin, a natural product of anthraquinone, is considered a potential antitumor drug. However, it has poor water solubility and low biological activity. In this study, we designed and synthesized a novel aloe emodin–hydroxyethyl piperazine hybrid dihydrochloride ( AE-NPC ), which improved the water solubility and antitumor activity of aloe emodin in vitro. According to the results, the IC 50 value of AE-NPC on CAL-27 cancer cells was 14.4 ± 2.9 μM. The flow cytometry results showed that AE-NPC induced the production of reactive oxygen species (ROS) and apoptosis in CAL-27 cells. The spectroscopy and molecular docking results showed that AE-NPC can be well intercalated into DNA grooves. Further molecular mechanism studies revealed that AE-NPC not only regulates the expression levels of key proteins (Bax/Bcl-2, cytochrome C, cleaved caspase-9 and cleaved caspase-3) of the mitochondrial apoptotic pathway but also activates the expression levels of a key protein ( γ -H 2 AX) of the DNA damage pathway. Therefore, AE-NPC induces CAL-27 cell apoptosis via DNA damage and mitochondrial pathways. This study provides new insights into the further development of anthraquinone compounds as potential chemotherapeutic agents for oral cancer treatment. The novel aloe emodin derivative AE-NPC induces oral cancer CAL-27 cells apoptosis through ROS production, DNA damage and mitochondrial pathways. The anthraquinone compound AE-NPC may be a potential agent for the treatment of oral cancer.