Eradication of KRAS mutant colorectal adenocarcinoma by PEGylated gold nanoparticles-cetuximab conjugates through ROS-dependent apoptosis

Abstract

Colorectal cancer (CRC) is a solid tumor with a high incidence and mortality rate worldwide. Excessive reactive oxygen species (ROS) seem to play a key role in CRC. As an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab (Cet) has been widely used in the immunotherapy of EGFR-positive CRC. However, the therapeutic response of Cet is limited mainly because of the emergence of multiple resistance mechanisms. To improve the cytotoxic impacts of Cet and induce apoptosis in CRC, in the current study, PEGylated gold nanoparticles (GNPs) conjugated with cetuximab (GNP-PEG-Cet) were developed to induce ROS-dependent apoptosis in cancer cells. The GNP-PEG-Cet nanoconjugates suppressed the growth of KRAS mutant SW-480 (G12V) CRC cells through induction of cell cycle arrest in the sub-G1 phase and apoptosis. The nanoconjugates significantly inhibited the Nrf2/Keap1/HO-1 pathway by increasing the expression level of Keap1 and decreasing the expression of Nerf2, CAT, and HO-1 in SW-480 cells compared to the untreated control cells. The engineered GNP-PEG-Cet nanoconjugates can interfere with the redox homeostasis in CRC cells and suppress the Nrf2-dependent antioxidant pathway resulting in a marked accumulation of ROS in cancer cells. Collectively, the GNP-PEG-Cet nanobiosystem may be considered an effective advanced multifunctional nanomedicine for the treatment of CRC and other solid tumors.