College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China.
Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, No. 452, Fengyuan Road, Panlong District, Kunming, 650201, China.
BMC Pharmacol Toxicol. 2023 May 11;24(1):29. doi: 10.1186/s40360-023-00661-2.
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.
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.
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.
Our data supported use of BBR in combination with erlotinib as a novel strategy for treatment of patients with EGFR positive tumors.
第一代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs），如厄洛替尼，已被证明可针对具有 L858R（外显子 21）和外显子 19 缺失的肿瘤，从而带来显著的临床获益。然而，由于 EGFR 突变，常常会发生获得性耐药。因此，需要新的治疗策略来治疗 EGFR 阳性肿瘤患者。小檗碱（BBR）是从黄连等药用植物中提取的一种活性生物碱。多项临床前研究表明，小檗碱可显著抑制 EGFR 活性并介导抗癌作用。我们研究了 BBR 与厄洛替尼联合应用是否可以增强 EGFR 阳性细胞在小鼠异种移植模型中的厄洛替尼诱导的细胞生长抑制作用。
我们通过 MTT 检测、免疫印迹、流式细胞术和肿瘤异种移植模型，在体外和体内研究了厄洛替尼联合小檗碱的抗肿瘤活性及其潜在机制。
体外 A431 细胞研究表明，BBR 与厄洛替尼联合应用的协同细胞生长抑制作用与显著增加的 pEGFR 和 pAKT 抑制以及细胞周期蛋白 D 和 Bcl-2 表达抑制有关，与单独使用 BBR 或厄洛替尼相比。我们还在裸鼠中研究了联合治疗的效果。与体外结果一致，BBR 加厄洛替尼显著降低了肿瘤生长。
我们的数据支持将 BBR 与厄洛替尼联合应用作为治疗 EGFR 阳性肿瘤患者的一种新策略。
