Department of First Clinical Medical College, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China; Department of Geriatrics, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, No. 54 Youdian Road, Hangzhou 310006, China.
J Ethnopharmacol. 2024 Nov 15;334:118586. doi: 10.1016/j.jep.2024.118586. Epub 2024 Jul 19.
Acquired resistance to osimertinib limits its clinical efficacy in non-small cell lung cancer (NSCLC) with EGFR mutations. The widespread recognition of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu (Chinese yew) as a natural anti-cancer medication is well-established. However, the specific contribution of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu in addressing resistance to osimertinib is still uncertain.
Based on the biological behaviors and lipid metabolism, we investigated whether aqueous extract of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu (AETC) could enhance the antitumor effect of osimertinib in NSCLC with an investigation on the precise mechanisms.
The effect of AETC on enhancing osimertinib sensitivity was assessed via cell viability measurements, levels of reactive oxygen species (ROS), apoptosis, and lipid levels. Western blotting was used to verify the mechanisms of AETC responsible for overcoming the resistance to osimertinib via ERK1/2 overexpression and knockdown models. In vivo validation was conducted using subcutaneous xenografts from osimertinib-resistant cells in nude mice.
Osimertinib-resistant cells exhibited altered cholesterol biosynthesis, which was induced by ERK1/2 activation. The combination of AETC and osimertinib can synergistically decrease the levels of ROS in cells, enhance apoptosis, and inhibit the growth of osimertinib-resistant cells. Mechanistic experiments demonstrated that AETC can downregulate the key regulators of cholesterol biosynthesis by regulating ERK1/2, inhibiting the endogenous synthesis rate of cholesterol, and suppressing the level of lipids in osimertinib-resistant cells and xenograft tumors when combined with osimertinib, ultimately reversing resistance to osimertinib.
The resistance to osimertinib is significantly influenced by cholesterol biosynthesis, highlighting its pivotal role in this context. AETC can enhance osimertinib sensitivity via ERK/SREBP-2/HMGCR-mediated cholesterol biosynthesis. These results provide a promising therapeutic target and potential treatment option for resistance to osimertinib.
奥希替尼获得性耐药限制了其在 EGFR 突变的非小细胞肺癌（NSCLC）中的临床疗效。广泛认识到红豆杉（中国紫杉）作为一种天然抗癌药物。然而，红豆杉（中国紫杉）在解决奥希替尼耐药方面的具体贡献尚不确定。
基于生物行为和脂质代谢，我们研究了红豆杉（中国紫杉）水提物（AETC）是否可以增强奥希替尼在 NSCLC 中的抗肿瘤作用，并探讨其确切机制。
通过细胞活力测定、活性氧（ROS）水平、细胞凋亡和脂质水平评估 AETC 增强奥希替尼敏感性的作用。使用 ERK1/2 过表达和敲低模型的 Western blot 验证 AETC 克服奥希替尼耐药的机制。在裸鼠奥希替尼耐药细胞的皮下异种移植模型中进行体内验证。
奥希替尼耐药细胞表现出胆固醇生物合成改变，这是由 ERK1/2 激活引起的。AETC 与奥希替尼联合使用可以协同降低细胞内 ROS 水平，增强细胞凋亡，抑制奥希替尼耐药细胞的生长。机制实验表明，AETC 通过调节 ERK1/2 下调胆固醇生物合成的关键调节因子，抑制胆固醇的内源性合成率，降低奥希替尼耐药细胞和异种移植肿瘤中的脂质水平，从而逆转奥希替尼耐药。
胆固醇生物合成对奥希替尼耐药有显著影响，强调了其在这方面的关键作用。AETC 可以通过 ERK/SREBP-2/HMGCR 介导的胆固醇生物合成增强奥希替尼的敏感性。这些结果为奥希替尼耐药提供了有前途的治疗靶点和潜在的治疗选择。
