LAUSR

Panitumumab is an approved monoclonal antibody for the treatment of colorectal cancer (CRC); however, mutations in EGFR signaling pathway resulted in poor response. Schisandrin‐B (Sch‐B) is a phytochemical that was suggested to protect against inflammation, oxidative stress, and cell proliferation. The present study aimed to investigate the potential effect of Sch‐B on panitumumab‐induced cytotoxicity in wild‐type Caco‐2, and mutant HCT‐116 and HT‐29 CRC cell lines, and the possible underlying mechanisms. CRC cell lines were treated with panitumumab, Sch‐B, and their combination. The cytotoxic effect of drugs was determined by MTT assay. The apoptotic potential was assessed in‐vitro by DNA fragmentation and caspase‐3 activity. Additionally, autophagy was investigated via microscopic detection of autophagosomes and quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) measurement of Beclin‐1, Rubicon, LC3‐II, and Bcl‐2 expression. The drug pair enhanced panitumumab cytotoxicity in all CRC cell lines where IC50 of panitumumab was decreased in Caco‐2 cell line. Apoptosis was induced through caspase‐3 activation, DNA fragmentation, and Bcl‐2 downregulation. Caco‐2 cell line treated with panitumumab showed stained acidic vesicular organelles, contrariwise, all cell lines treated with Sch‐B or the drug pair displayed green fluorescence indicating the lack of autophagosomes. qRT‐PCR revealed the downregulation of LC3‐II in all CRC cell lines, Rubicon in mutant cell lines, and Beclin‐1 in HT‐29 cell line only. Sch‐B at 6.5 µM promoted panitumumab‐induced apoptotic cell death, in‐vitro, via caspase‐3 activation and Bcl‐2 downregulation, rather than autophagic cell death. This novel combination therapy against CRC, allows the reduction of panitumumab dose to guard against its adverse effects.