Li Hefei, Zhang Yushan, Lan Xiaomei, Yu Jianhua, Yang Changshuang, Sun Zhijian, Kang Ping, Han Yi, Yu Daping
Department of Thoracic Surgery, Affiliated Hospital of Hebei University, Baoding, China.
Department of Thoracic Surgery, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China.
Front Cell Dev Biol. 2021 Nov 24;9:773048. doi: 10.3389/fcell.2021.773048. eCollection 2021.
Lung cancer is the leading cause of cancer death worldwide. Cisplatin is the major DNA-damaging anticancer drug that cross-links the DNA in cancer cells, but many patients inevitably develop resistance with treatment. Identification of a cisplatin sensitizer might postpone or even reverse the development of cisplatin resistance. Halofuginone (HF), a natural small molecule isolated from , has been found to play an antitumor role. In this study, we found that HF inhibited the proliferation, induced G0/G1 phase arrest, and promoted apoptosis in lung cancer cells in a dose-dependent manner. To explore the underlying mechanism of this antitumor effect of halofuginone, we performed RNA sequencing to profile transcriptomes of NSCLC cells treated with or without halofuginone. Gene expression profiling and KEGG analysis indicated that PI3K/AKT and MAPK signaling pathways were top-ranked pathways affected by halofuginone. Moreover, combination of cisplatin and HF revealed that HF could sensitize the cisplatin-resistant patient-derived lung cancer organoids and lung cancer cells to cisplatin treatment. Taken together, this study identified HF as a cisplatin sensitizer and a dual pathway inhibitor, which might provide a new strategy to improve prognosis of patients with cisplatin-resistant lung cancer.
肺癌是全球癌症死亡的主要原因。顺铂是主要的DNA损伤抗癌药物，可使癌细胞中的DNA交联，但许多患者在治疗过程中不可避免地会产生耐药性。鉴定一种顺铂增敏剂可能会延缓甚至逆转顺铂耐药性的发展。常山酮（HF）是一种从[具体来源未给出]中分离出的天然小分子，已被发现具有抗肿瘤作用。在本研究中，我们发现HF以剂量依赖的方式抑制肺癌细胞的增殖，诱导G0/G1期阻滞，并促进其凋亡。为了探究常山酮这种抗肿瘤作用的潜在机制，我们进行了RNA测序，以分析用或不用常山酮处理的非小细胞肺癌（NSCLC）细胞的转录组。基因表达谱分析和KEGG分析表明，PI3K/AKT和MAPK信号通路是受常山酮影响最显著的信号通路。此外，顺铂与HF联合使用表明，HF可使顺铂耐药的患者来源的肺癌类器官和肺癌细胞对顺铂治疗敏感。综上所述，本研究确定HF为一种顺铂增敏剂和双通路抑制剂，这可能为改善顺铂耐药肺癌患者的预后提供一种新策略。
