Hsu Jade H-M, Chang Peter M-H, Cheng Tai-Shan, Kuo Yu-Lun, Wu Alexander T-H, Tran Thu-Ha, Yang Yun-Hsuan, Chen Jing-Ming, Tsai Yu-Chen, Chu Yeh-Shiu, Huang Tse-Hung, Huang Chi-Ying F, Lai Jin-Mei
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Cancers (Basel). 2019 Jul 17;11(7):1003. doi: 10.3390/cancers11071003.
Low response rate and recurrence are common issues in lung cancer; thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from , as a potential anti-lung cancer and anti-lung cancer stem-like cell (CSC) agent. First, we demonstrated that WA exhibited potent cytotoxicity in several lung cancer cells, as evidenced by low IC values. WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects. The increase in p62 indicated that WA may modulate the autophagy flux followed by apoptosis. research also demonstrated the anti-tumor effect of WA treatment. We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity, at least through downregulation of mTOR/STAT3 signaling. Furthermore, the combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability. In addition, WA can further enhance the cytotoxic effect of cisplatin in lung CSCs. Therefore, WA alone or in combination with standard chemotherapy is a potential treatment option for EGFR wild-type lung cancer and may decrease the occurrence of cisplatin resistance by inhibiting lung CSCs.
低反应率和复发是肺癌常见的问题；因此，为这些患者确定一种潜在的化合物至关重要。利用计算机模拟筛选方法，我们确定了从 中最初提取的细胞可渗透甾体内酯穿心莲内酯A（WA）作为一种潜在的抗肺癌和抗肺癌干细胞（CSC）药物。首先，我们证明WA在几种肺癌细胞中表现出强大的细胞毒性，低IC值证明了这一点。WA同时诱导自噬和凋亡以及活性氧（ROS）的激活，ROS在介导WA引发的效应中起上游作用。p62的增加表明WA可能调节自噬通量继而引发凋亡。 研究还证明了WA治疗的抗肿瘤作用。我们随后证明WA可以抑制肺癌CSCs的生长，减少侧群细胞，并抑制肺癌球体形成能力，至少通过下调mTOR/STAT3信号通路。此外，WA与包括顺铂和培美曲塞在内的化疗药物联合使用，对抑制表皮生长因子受体（EGFR）野生型肺癌细胞活力发挥协同作用。此外，WA可以进一步增强顺铂对肺癌CSCs的细胞毒性作用。因此，单独使用WA或与标准化疗联合使用是EGFR野生型肺癌的一种潜在治疗选择，并且可能通过抑制肺癌CSCs来降低顺铂耐药性的发生。
