Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways

Colorectal cancer (CRC) remains one of the most common gastrointestinal tumors, characterized by a poor survival rate. Effects of single use of homoharringtonine (HHT), approved for the treatment of acute myelocytic leukemia (AML) and chronic myeloid leukemia (CML), on CRC, are unknown. According to the TCGA database, EphB4 is aberrantly overexpressed in CRC patients. Therefore, the purpose of this study was to investigate the inhibitory effect of HHT on CRC and its underlying mechanism. HHT significantly suppressed LoVo cell growth in vitro and in vivo, and induced apoptosis and cell cycle arrest at the S phase. Mechanistic investigation using western blotting revealed that HHT suppressed EphB4, and this suppression was augmented by both HHT and NVP-BHG712 co-administration and EphB4 overexpression, indicating that HHT targets EphB4 to suppress LoVo cell growth. HHT inhibited EphB4 downstream pathways such as PI3K/AKT and MAPK/EKR1/2, resulting in the regulation of cell cycle-related molecules (cyclinA2 and CDC2), and the molecules in the Bcl-2 mitochondrial apoptosis pathway including Bcl-2, Mcl-1, Bax, Bad, caspase-3, caspase-7, and caspase-9. HHT may therefore be a promising EphB4 inhibitor with great potential for CRC treatment.