Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Cancer Med. 2024 Oct;13(19):e70271. doi: 10.1002/cam4.70271.
Despite significant advances in lung cancer treatment, cisplatin (DDP)-based chemotherapy remains a cornerstone for managing the disease. However, the prevalence of chemoresistance presents a major challenge, limiting its effectiveness and contributing to poor outcomes. This underscores the urgent need for novel therapeutic strategies to overcome chemoresistance and improve chemotherapy efficacy in lung cancer patients. Exploring approaches to sensitize tumors to cisplatin could enhance treatment responses and overall survival rates.
Our study utilized a variety of lung cancer models, including cell lines, mouse models, and patient-derived organoids, to validate the synergistic cytotoxic effects of dihydroartemisinin (DHA) and cisplatin (DDP). When combined with DDP, we demonstrate that DHA is a promising therapeutic agent that effectively triggers ferroptosis in lung cancer cells, offering a potential strategy for overcoming chemoresistance. Mechanistically, the combination of DHA and DDP synergistically enhances ZIP14 expression, modulating iron homeostasis and upregulating oxidative stress, leading to both in vitro and in vivo ferroptosis. Notably, our findings revealed that the sequential administration of DDP followed by DHA significantly increases ZIP14 expression and induces superior therapeutic outcomes compared to the simultaneous administration or DHA followed by DDP. This observation underscores the importance of the drug administration order in optimizing treatment efficacy, providing new insights into enhancing chemotherapy response in lung cancer.
Our findings suggest that combining dihydroartemisinin (DHA) with cisplatin (DDP) presents a promising strategy to overcome chemoresistance in lung cancer patients. Importantly, administering DHA during chemotherapy intervals could further optimize treatment outcomes, enhancing the overall efficacy of lung cancer chemotherapy.
尽管肺癌治疗取得了重大进展，但顺铂（DDP）为基础的化疗仍然是治疗该疾病的基石。然而，化疗耐药的普遍存在是一个主要挑战，限制了其疗效，并导致预后不良。这突显了迫切需要新的治疗策略来克服化疗耐药性，提高肺癌患者的化疗效果。探索使肿瘤对顺铂敏感的方法可以增强治疗反应和总生存率。
我们的研究利用了多种肺癌模型，包括细胞系、小鼠模型和患者来源的类器官，来验证二氢青蒿素（DHA）和顺铂（DDP）联合使用的协同细胞毒性作用。当与 DDP 联合使用时，我们证明 DHA 是一种有前途的治疗药物，它可以有效地触发肺癌细胞中的铁死亡，为克服化疗耐药性提供了一种潜在策略。从机制上讲，DHA 和 DDP 的联合使用协同增强了 ZIP14 的表达，调节铁稳态并上调氧化应激，导致体外和体内铁死亡。值得注意的是，我们的研究结果表明，DDP 序贯给药后再给予 DHA 可显著增加 ZIP14 的表达，并诱导优于同时给药或 DHA 序贯给药的治疗效果。这一观察结果强调了优化治疗效果的药物给药顺序的重要性，为增强肺癌化疗反应提供了新的见解。
我们的研究结果表明，将二氢青蒿素（DHA）与顺铂（DDP）联合使用是克服肺癌患者化疗耐药性的一种很有前途的策略。重要的是，在化疗期间给予 DHA 可以进一步优化治疗效果，提高肺癌化疗的整体疗效。
