Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey.
Department of Pediatric Surgery, School of Medicine, Marmara University, Pendik, Istanbul, Turkey.
Cell Biol Int. 2020 Sep;44(9):1934-1944. doi: 10.1002/cbin.11399. Epub 2020 May 31.
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.
恶性间皮瘤是一种罕见但侵袭性的恶性肿瘤，难以诊断，并且对目前的化学治疗选择具有抗药性。分子技术已被用于研究哈罗芬酮（HF）在几种癌症中的作用机制和有益的治疗效果，但尚未用于恶性间皮瘤。在这项研究中，通过研究 HF 对病理性侵袭性恶性间皮瘤和非小细胞肺癌细胞中 EGFR 下游信号级联蛋白的调节作用，研究了 HF 的抗增殖和促凋亡作用。我们表明，HF 以纳摩尔浓度给药会诱导癌细胞活力的剂量依赖性降低，使细胞周期停滞，通过 STAT3 和 ERK1/2 途径抑制癌细胞增殖，并通过 p38MAPK 触发凋亡级联。我们证明，凋亡细胞死亡机制是通过增强 caspase-3 的激活和伴随的 PARP 切割，下调 Bcl-2 和上调 Bax 在恶性间皮瘤和肺癌细胞中介导的。特别是，我们证明癌细胞比正常间皮细胞对 HF 治疗更敏感。总之，这项研究表明，HF 通过主要通过调节 ERK1/2、STAT3 和 p38MAPK 来降低癌细胞活力、诱导细胞周期停滞和促凋亡细胞死亡，从而发挥其在肺源性癌症中的抗癌作用。因此，HF 可能被认为是一种针对恶性间皮瘤和/或肺癌细胞的潜在药物。
