Synergistic Anticancer Effects of Lenvatinib and Celastrol via Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress and JNK Signaling in Colon Cancer Cells.

Purpose: Colon cancer, a predominant contributor to global cancer mortality, is characterized by uncontrolled cell growth in the colon or rectum. Therapeutic progress notwithstanding, including targeted therapies and chemotherapy, the survival rate remains unsatisfactory, especially for patients with advanced colon cancer, underscoring the need for novel strategies to enhance treatment efficacy. Materials and Methods: In this study, we employed Western blot analysis to quantify target protein expression levels and immunofluorescence for protein detection and localization. To evaluate drug interactions, we calculated the Combination Index. Intracellular reactive oxygen species (ROS) levels were measured using the DCFH-DA probe. Additionally, we generated target gene-knockdown cell lines via recombinant lentivirus transfection. For in vivo validation, we established a xenograft tumor model in nude mice to assess the therapeutic efficacy of the drug combination. Results: In the study, we systematically evaluated the combinatorial potential of clinically approved lenvatinib and bioactive celastrol against colorectal cancer pathogenesis. Our results demonstrated that the combination treatment significantly inhibited cancer cell proliferation by enhancing ROS generation. This oxidative stress activated the ATF4-CHOP and JNK signaling pathways, ultimately inducing cell apoptosis as the main cause of death phenomenon. Conclusion: Our research demonstrates that celastrol potentiates lenvatinib's anti-tumor effects in colon cancer by inducing ROS-dependent endoplasmic reticulum stress and triggering phosphorylation-dependent JNK pathway activation. These findings reveal a promising combinatorial strategy to enhance therapeutic efficacy in colorectal carcinoma.