Berberine: a promising strategy to combat cetuximab-resistance in colorectal cancer.

Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is approved as a front-line treatment for metastatic colorectal cancers, but limited efficacy is obtained. Combinatory therapy is a potentially promising strategy to enhance anticancer effects, overcome drug resistance and improve overall clinical survival. Here, we show that berberine combined with cetuximab created a synergistic inhibitory effect on cetuximab-resistant CRC cells in vitro and in vivo. Human phospho-kinase assay explored that the phosphorylation of Src and Chk-2 was inhibited by berberine and decreased greatly when combined with cetuximab. Adding KX2-391 (Src inhibitor) rather than BML-277 (Chk-2 inhibitor) with cetuximab resulted in more cell death and apoptosis. Conversely, activation of Src with MLR-1023 mitigated the inhibitory effect of berberine alone or in combination with cetuximab. Additionally, the activities of downstream kinases of Src such as mTOR, STAT3 and the production of ROS were inhibited greatly by berberine plus cetuximab. Taken together, we concluded that the synergistic effects of BBR and cetuximab may be mediated by decreasing the activities of Src/mTOR/STAT3 and the production of ROS, thus inducing greater extent of apoptosis in cancer cells.