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Antitumor effects of erlotinib in combination with berberine in A431 cells
Xiangdan Cuan1, Xingying Yang1, Weiwei Zhu1
1College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China.
Background:
First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, have been shown to target tumors with L858R (exon 21) and exon 19 deletions, resulting in significant clinical benefits. However, acquired resistance often occurs due to EGFR mutations. Therefore, novel therapeutic strategies for treatment of patients with EGFR-positive tumors are needed. Berberine (BBR) is an active alkaloid extracted from pharmaceutical plants such as Coptis chinensis. Berberine has been shown to significantly inhibit EGFR activity and mediate anticancer effects in multiple preclinical studies. We investigated whether combining BBR with erlotinib could augment erlotinib-induced cell growth inhibition of EGFR-positive cells in a mouse xenograft model.
Methods:
We examined the antitumor activities and potential mechanisms of erlotinib in combination with berberine in vitro and in vivo using the MTT assay, immunoblotting, flow cytometry, and tumor xenograft models.
Results:
In vitro studies with A431 cells showed that synergistic cell growth inhibition by the combination of BBR and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, and inhibition of cyclin D and Bcl-2 expression compared to that observed in response to BBR or erlotinib alone. The efficacy of the combination treatment was also investigated in nude mice. Consistent with the in vitro results, BBR plus erlotinib significantly reduced tumor growth.
Conclusion:
Our data supported use of BBR in combination with erlotinib as a novel strategy for treatment of patients with EGFR positive tumors.
Insights
Combining berberine (BBR) with erlotinib offers a novel strategy to enhance cancer treatment for EGFR-positive tumors. This combination therapy demonstrated synergistic cell growth inhibition and reduced tumor growth in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- First-generation EGFR-TKIs like erlotinib are effective against EGFR mutations (L858R, exon 19 deletions) but acquired resistance limits efficacy.
- Novel therapeutic strategies are crucial for treating patients with EGFR-positive tumors, especially those developing resistance.
- Berberine (BBR), a natural alkaloid, exhibits preclinical anticancer effects by inhibiting EGFR activity.
Purpose of the Study:
- To investigate the potential of combining berberine (BBR) with erlotinib to enhance the inhibition of EGFR-positive cancer cells.
- To evaluate the synergistic effects and underlying mechanisms of BBR and erlotinib combination therapy in vitro and in vivo.
Main Methods:
- In vitro studies utilized MTT assays and immunoblotting to assess cell viability and protein expression (pEGFR, pAKT, cyclin D, Bcl-2).
- Flow cytometry was employed to analyze cellular effects.
- In vivo efficacy was evaluated using a mouse xenograft model to assess tumor growth inhibition.
Main Results:
- The combination of BBR and erlotinib demonstrated synergistic inhibition of A431 cell growth in vitro.
- Combined treatment led to greater inhibition of pEGFR, pAKT, cyclin D, and Bcl-2 compared to monotherapy.
- BBR plus erlotinib significantly reduced tumor growth in the mouse xenograft model.
Conclusions:
- The combination of berberine and erlotinib shows promise as a novel therapeutic strategy for EGFR-positive tumors.
- This combination enhances the efficacy of erlotinib by targeting key signaling pathways involved in cell proliferation and survival.
- Further clinical investigation is warranted to validate these findings in patients with EGFR-positive cancers.
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