Griffithazanone A, a sensitizer of EGFR-targeted drug in Goniothalamus yunnanensis for non-small cell lung cancer
Ting Xiao,
Yuxin Zhu,
Liang Zhang,
Kaidi Xiao,
Xiao Jia,
Yashu Liu,
Junfang Bi,
Xiaoping Li,
Honggang Zhou,
Cheng Yang
Affiliations
Ting Xiao
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
Yuxin Zhu
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; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China
Liang Zhang
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
Kaidi Xiao
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; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China
Xiao Jia
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
Yashu Liu
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; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China
Junfang Bi
Department of Combined Traditional Chinese Medicine and West Medicine, Traditional Chinese Medicine Hospital of Shijiazhuang City, Shijiazhuang, 050051, China
Xiaoping Li
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; Corresponding author.
Honggang Zhou
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; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China; Corresponding author. 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.
Cheng Yang
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; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China; Corresponding author. 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.
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 (1–7) and two styryllactones (8 and 9) were isolated from twigs and leaves of Goniothalamus yunnanensis. Their structures were elucidated by their NMR spectroscopic data. Among them, griffithazanone A (1) showed the strongest inhibitory activity with the IC50 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 in vitro and in vivo. 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.
