Lu Jing, Zhang Ying, Yan Chunyan, Liu Jingwen, Qi Dan, Zhou Yue, Wang Qinwen, Yang Juechen, Jiang Jing, Wu Benhao, Yang Meiling, Zhang Weiwei, Zhang Xin, Shi Xiaoyu, Zhang Yan, Liu Kun, Liang Yongcai, Wang Chaoyang, Yang Hanyu, Gao Yuqing, Sun Yuping, Ke Ronghu, Huang Jason H, Wu Min, Wang Hongbo, Li Chunlei, Zhou Shuang, Guo Bin, Wu Erxi, Zhang Guoying
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China.
Shandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, China.
Bioact Mater. 2024 Dec 13;45:567-583. doi: 10.1016/j.bioactmat.2024.11.019. eCollection 2025 Mar.
Despite significant advances in targeted therapies and immunotherapies, non-small cell lung cancer (NSCLC) continues to present a global health challenge, with a modest five-year survival rate of 28 %, largely due to the emergence of treatment-resistant and metastatic tumors. In response, we synthesized a novel bioactive compound, ethyl 6-chlorocoumarin-3-carboxylyl L-theanine (TClC), which significantly inhibited NSCLC growth, epithelial mesenchymal transition (EMT), migration, and invasion and tumor growth and metastasis without inducing toxicity. TClC disrupts autocrine loops that promote tumor progression, particularly in stem-like CD133-positive NSCLC (CD133+ LC) cells, which are pivotal in tumor metastasis. Through targeted molecular assays, we identified direct binding targets of TClC, including Akt, NF-κB, β-catenin, EZH2, and PD-L1. This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter, underscoring the compound's polypharmacological potential. These results position TClC as a promising candidate for NSCLC treatment, signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways.
尽管在靶向治疗和免疫治疗方面取得了重大进展，但非小细胞肺癌（NSCLC）仍然是一项全球性的健康挑战，其五年生存率仅为28%，且生存率增长幅度不大，这主要是由于出现了对治疗耐药的转移性肿瘤。作为应对措施，我们合成了一种新型生物活性化合物——6-氯香豆素-3-羧基-L-茶氨酸乙酯（TClC），该化合物能显著抑制NSCLC的生长、上皮-间质转化（EMT）、迁移和侵袭以及肿瘤生长和转移，且不会产生毒性。TClC破坏了促进肿瘤进展的自分泌环，尤其是在肿瘤转移中起关键作用的干细胞样CD133阳性NSCLC（CD133+ LC）细胞中。通过靶向分子检测，我们确定了TClC的直接结合靶点，包括Akt、NF-κB、β-连环蛋白、EZH2和PD-L1。这种相互作用不仅抑制致癌因子和癌症干细胞标志物的表达，还下调多药耐药转运蛋白的表达，凸显了该化合物的多药理学潜力。这些结果表明TClC有望成为NSCLC治疗的候选药物，标志着直接靶向多种关键癌症通路的癌症治疗新时代的到来。
