Shikonin potentiates therapeutic efficacy of oxaliplatin through reactive oxygen species‐mediated intrinsic apoptosis and endoplasmic reticulum stress in oxaliplatin‐resistant colorectal cancer cells

Abstract Oxaliplatin (OXA) has been recognized as a third‐generation platinum‐based chemotherapeutic agent with stellar therapeutic efficacy in managing colorectal cancer (CRC). Nevertheless, resistance to OXA in CRC patients hinders its effectiveness. Shikonin (SHI), a natural naphthoquinone derived from Arnebia euchroma (Royle) Johnst. , features a broad pharmacological profile and minimal toxicities. To assess the synergism of SHI and OXA towards OXA‐resistant CRC cells (HCT116 R ), we employed in vitro and in vivo pharmacological assays. Our experiments provided evidence that SHI, either alone or in combination with OXA, considerably reduced cell proliferation, triggered apoptosis, and induced the generation of reactive oxygen species (ROS) in HCT116 R cells. Furthermore, the combination of SHI and OXA dramatically curbed the extent of HCT116 R ‐initiated xenograft growth in mouse models. Bioinformatics, western blot, and ROS assays highlighted that the mechanisms of SHI against OXA‐resistant CRC cells may involve the induction of cellular responses to chemical stress, intrinsic apoptosis, as well as endoplasmic reticulum stress pathways mediated by ROS. Notably, the synergism of SHI+OXA was partially abrogated by an ROS inhibitor N‐acetyl cysteine. Our findings imply the potential of SHI to boost the sensitivity of OXA to CRC, offering promising benefits for clinical strategies to combat OXA resistance.