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<p>Cetuximab, a monoclonal antibody against epidermal growth factor receptor (<i>EGFR</i>), 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 <i>Src</i> and <i>Chk-2</i> was inhibited by berberine and decreased greatly when combined with cetuximab. Adding KX2-391 (<i>Src</i> inhibitor) rather than BML-277 (<i>Chk-2</i> inhibitor) with cetuximab resulted in more cell death and apoptosis. Conversely, activation of <i>Src</i> with MLR-1023 mitigated the inhibitory effect of berberine alone or in combination with cetuximab. Additionally, the activities of downstream kinases of <i>Src</i> such as <i>mTOR</i>, <i>STAT3</i> 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 <i>Src/mTOR/STAT3</i> and the production of ROS, thus inducing greater extent of apoptosis in cancer cells.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Jianmin Ye,
  • Bingchan Sun,
  • Fengmei Xia,
  • Guoxin Wang,
  • Huimin Liu,
  • Jianghua Ding,
  • Mingfu Tong

摘要

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.