Malignant mesothelioma is a rare but aggressive form of malignancy, which is difficult to diagnose and is resistant to current chemotherapeutic treatment options. Molecular techniques have been used to investigate the mechanisms of action and the beneficial therapeutic effects of halofuginone (HF) in several cancers but not malignant mesotheliomas. In this study, the antiproliferative and apoptotic effects of HF were investigated through its ability to deregulate EGFR downstream signalling cascade proteins in the pathologically aggressive malignant mesothelioma and non‐small‐cell lung cancer cells. We showed that administration of HF at nanomolar concentrations induced a dose‐dependent reduction in the viability of cancer cells, made cell cycle arrest, inhibited proliferation of cancer cells via STAT3 and ERK1/2 pathways and triggered the apoptotic cascade via p38MAPK. We demonstrated that the apoptotic cell death mechanism was mediated by enhanced activation of caspase‐3 and concomitant PARP cleavage, downregulation of Bcl‐2 and upregulation of Bax in both malignant mesothelioma and lung cancer cells. In particular, we demonstrated that cancer cells were more sensitive to HF treatment than normal mesothelial cells. Taken together, this study suggests that HF exerts its anticancer effects in lung‐derived cancers by targeting signal transduction pathways mainly through deregulation of ERK1/2, STAT3 and p38MAPK to reduce cancer cell viability, induce cell cycle arrest and apoptotic cell death. Thus, HF might be considered as a potential agent against malignant mesothelioma and/or lung cancer cells.

中文翻译：

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氟丁酮对肺癌细胞的抗癌作用。

恶性间皮瘤是一种罕见但侵袭性的恶性肿瘤，难以诊断且对目前的化疗方法有抵抗力。分子技术已被用于研究氟丁酮（HF）在几种癌症中的作用机理和有益的治疗作用，但对恶性间皮瘤没有作用。在这项研究中，通过在病理性侵袭性恶性间皮瘤和非小细胞肺癌细胞中通过调节HF下游下游信号级联蛋白的能力来研究HF的抗增殖和凋亡作用。我们发现以纳摩尔浓度施用HF会导致癌细胞活力呈剂量依赖性降低，从而使细胞周期停滞，通过STAT3和ERK1 / 2途径抑制癌细胞的增殖，并通过p38MAPK触发凋亡级联反应。我们证明凋亡细胞死亡机制是由恶性间皮瘤和肺癌细胞中增强的caspase-3激活和伴随的PARP裂解，Bcl-2的下调以及Bax的上调介导的。特别是，我们证明了癌细胞比正常的间皮细胞对HF治疗更敏感。综上所述，这项研究表明，HF主要通过使ERK1 / 2，STAT3和p38MAPK失调来靶向信号转导途径，从而降低癌细胞的活力，诱导细胞周期停滞和凋亡，从而在肺癌衍生的癌症中发挥抗癌作用。从而，