Cinnamaldehyde induces apoptosis and enhances anti‐colorectal cancer activity via covalent binding to HSPD1

Abstract Colorectal cancer (CRC) is a common malignant tumor with high morbidity and mortality rates worldwide. Although surgical resection and adjuvant radiotherapy/chemotherapy are the mainstays of CRC treatment, the efficacy is unsatisfactory due to several limitations, including high drug resistance. Accordingly, there is a dire need for new drugs or a novel combination approach to treat this patient population. Herein, we found that cinnamaldehyde (CA) could exert an antitumor effect in HCT‐116 cell lines. Target fishing, molecular imaging, and live‐cell tracing using an alkynyl–CA probe revealed that the heat shock 60 kDa protein 1 (HSPD1) protein was the target of CA. The covalent binding of CA with HSPD1 altered its stability. Furthermore, our results demonstrated that CA could induce cell apoptosis by inhibiting the PI3K/Akt signaling pathway and enhanced anti‐CRC activity both in vitro and in vivo. Meanwhile, CA combined with different chemotherapeutic agents was beneficial to patients resistant to anti‐CRC drug therapy.