Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan.
Orthopedics & Sports Medicine Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan.
Molecules. 2018 Aug 23;23(9):2121. doi: 10.3390/molecules23092121.
Inhibition of proliferating cells is a critical strategy for cancer therapy. In this study, we demonstrated that coronarin D, a natural component extracted from the rhizomes of , significantly suppressed the proliferation of osteosarcoma cells. The treatment with coronarin D resulted in the activation of caspase-3 and apoptosis. This treatment induced the accumulation of cyclin B1 and DNA condensation indicating the treated osteosarcoma cells were arrested in mitotic phase. Furthermore, the treatment with coronarin D increased the levels of phosphorylated c-Jun NH2-terminal kinase (JNK) in human osteosarcoma cells. Pretreatment with JNK inhibitor blocked the accumulation of cyclin B1 and DNA condensation, resulting the accumulation of tetraploid cells in coronarin D-treated osteosarcoma HOS cells, indicating JNK inactivation blocked the mitotic entry and arrested cells in the 4 N state. After adaptation, the arrested tetraploid cells continued to duplicate their DNA resulting in polyploidy. Interestingly, when the arrested mitotic cells induced by coronarin D were treated with JNK inhibitor, the accumulated cyclin B1 and DNA condensation were immediately eliminated. These arrested 4 N cells loss the ability to undergo cytokinesis, and ultimately continued to duplicate DNA upon prolonged arrest resulting in the production of polyploid populations. JNK inactivation, either by the pretreatment with JNK inhibitor or the treatment with JNK inhibitor in coronarin D-induced mitotic cells, both caused resistance to coronarin D-induced cell death. Taken together, our findings indicate that coronarin D induces the apoptosis and mitosis arrest in human osteosarcoma cells. JNK has a crucial role in coronarin D-induced mitosis arrest and apoptosis. We hypothesize that functional evaluation of JNK may produce more specific and effective therapies in coronarin D-related trail for treatment of human osteosarcoma.
抑制增殖细胞是癌症治疗的关键策略。在这项研究中，我们证明了 coronarin D，一种从 中提取的天然成分，能显著抑制骨肉瘤细胞的增殖。coronarin D 的处理导致 caspase-3 的激活和细胞凋亡。这种处理导致 cyclin B1 的积累和 DNA 凝聚，表明处理过的骨肉瘤细胞在有丝分裂期被阻滞。此外，coronarin D 处理增加了人骨肉瘤细胞中磷酸化 c-Jun NH2-末端激酶 (JNK) 的水平。JNK 抑制剂预处理阻断了 cyclin B1 和 DNA 凝聚的积累，导致 coronarin D 处理的骨肉瘤 HOS 细胞中四倍体细胞的积累，表明 JNK 失活阻断了有丝分裂进入并使细胞停滞在 4N 状态。适应后，被阻滞的四倍体细胞继续复制其 DNA，导致多倍体。有趣的是，当 coronarin D 诱导的有丝分裂细胞被 JNK 抑制剂处理时，积累的 cyclin B1 和 DNA 凝聚立即被消除。这些被阻滞的 4N 细胞失去了进行胞质分裂的能力，并且在长时间阻滞后继续复制 DNA，导致多倍体群体的产生。JNK 失活，无论是通过 JNK 抑制剂的预处理还是在 coronarin D 诱导的有丝分裂细胞中 JNK 抑制剂的处理，都导致对 coronarin D 诱导的细胞死亡的抗性。总之，我们的研究结果表明 coronarin D 诱导人骨肉瘤细胞凋亡和有丝分裂阻滞。JNK 在 coronarin D 诱导的有丝分裂阻滞和凋亡中起着关键作用。我们假设 JNK 的功能评估可能会在 coronarin D 相关的临床试验中产生更特异和有效的治疗方法，用于治疗人骨肉瘤。
