Xiao Ting, Zhu Yuxin, Zhang Liang, Xiao Kaidi, Jia Xiao, Liu Yashu, Bi Junfang, Li Xiaoping, Zhou Honggang, Yang Cheng
State Key Laboratory of Separation Membranes and Membrane Processes, Tianjin Key Laboratory of Green Chemical Technology and Process Engineering, School of Pharmaceutical Sciences, Tiangong University, Tianjin, 300387, China.
State Key Laboratory of Medicinal Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Department of Thoracic Surgery, Tianjin First Central Hospital, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China.
Heliyon. 2024 Sep 26;10(19):e38489. doi: 10.1016/j.heliyon.2024.e38489. eCollection 2024 Oct 15.
Non-small cell lung cancer (NSCLC), which accounts for up to 85 % of lung cancer cases, significantly impacts the health of individuals worldwide. While targeted therapy has played a crucial role, the emergence of EGFR resistance and adverse reactions has made it imperative to explore new medications. Natural products derived from plants became an important source of anti-tumor drugs. In this study, nine known compounds, including seven alkaloids (-) and two styryllactones ( and ) were isolated from twigs and leaves of Their structures were elucidated by their NMR spectroscopic data. Among them, griffithazanone A () showed the strongest inhibitory activity with the IC value of 6.775 μM. Our findings revealed that griffithazanone A treatment induced cytotoxicity, apoptosis, and ROS generation in A549 cells in a dose-dependent manner. It regulates the expression of apoptosis-related proteins Bax, Bcl-2, and cleaved-caspase3 both and . Further investigation demonstrated that griffithazanone A regulated the proteins involved in the ASK1/JNK/p38 and BAD/Bcl-2 pathways in A549 cells by targeting PIM1. Moreover, griffithazanone A treatment enhanced the efficacy of gefitinib and osimertinib and reversed osimertinib resistance. Overall, our study highlights the potential of griffithazanone A in inhibiting the progression of NSCLC by targeting PIM1 and reversing resistance to EGFR targeted drugs.
非小细胞肺癌（NSCLC）占肺癌病例的85%，对全球个人健康有重大影响。虽然靶向治疗发挥了关键作用，但表皮生长因子受体（EGFR）耐药性和不良反应的出现使得探索新药物势在必行。植物来源的天然产物成为抗肿瘤药物的重要来源。在本研究中，从[植物名称]的嫩枝和叶子中分离出9种已知化合物，包括7种生物碱（-）和2种苯乙烯内酯（[具体名称1]和[具体名称2]）。通过核磁共振光谱数据阐明了它们的结构。其中，格氏内酯A（[具体结构简式]）表现出最强的抑制活性，IC值为6.775μM。我们的研究结果表明，格氏内酯A处理以剂量依赖性方式诱导A549细胞的细胞毒性、凋亡和活性氧生成。它在体内和体外均调节凋亡相关蛋白Bax、Bcl-2和裂解的半胱天冬酶3的表达。进一步研究表明，格氏内酯A通过靶向PIM1调节A549细胞中与ASK1/JNK/p38和BAD/Bcl-2途径相关的蛋白。此外，格氏内酯A处理增强了吉非替尼和奥希替尼的疗效并逆转了奥希替尼耐药性。总体而言，我们的研究突出了格氏内酯A通过靶向PIM1抑制NSCLC进展和逆转对EGFR靶向药物耐药性的潜力。
