Fu Yun, Liu Youxun, Wang Jiangang, Li Cuiping, Zhou Sufeng, Yang Yun, Zhou Pingxin, Lu Chengbiao, Li Changzheng
Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
Department of Pathophysiology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
Oncol Rep. 2017 Mar;37(3):1662-1670. doi: 10.3892/or.2017.5395. Epub 2017 Jan 20.
Thiosemicarbazones display significant antitumor activity and their copper complexes also exhibit enhanced biological activities in most situations, but the underlying mechanism is poorly understood. Therefore, investigation of the mechanism involved in the change upon chelation is required to extend our understanding of the effects of thiosemicarbazones. In the present study, the inhibitory effect of 2-pyridinecarboxaldehyde thiosemicarbazone (PCT) and its copper complex (PCT-Cu) on cell proliferation was investigated. The copper chelate exhibited a 3- to 10-fold increase in antitumor activity (with an IC50 <5 µM). The results showed that both PCT and PCT-Cu induced reactive oxygen species (ROS) generation in vitro and in vivo, caused cellular DNA fragmentation, depolarization of the mitochondrial membrane and cell cycle arrest. Western blotting showed that both PCT and PCT-Cu induced apoptosis. Upregulation of GRP78 in HepG2 cells following treatment with the agents indicated that endoplasmic reticulum (ER) stress occurred. Furthermore calcium release was revealed in this study, suggesting that PCT and PCT-Cu disturbed calcium homeostasis. It was noted that PCT-Cu sensitized thapsigargin‑stimulated calcium release from the ER, which was correlated with the ROS level they induced, implying that the antitumor activity of PCT and PCT-Cu partly stemmed from calcium mobilization, a situation that was reported in few studies. Our findings may significantly contribute to the understanding of the anti‑proliferative effect of the derivatives of thiosemicarbazones along with their antitumor mechanism.
硫代氨基脲显示出显著的抗肿瘤活性，并且它们的铜配合物在大多数情况下也表现出增强的生物活性，但其潜在机制尚不清楚。因此，需要研究螯合作用所涉及的机制，以加深我们对硫代氨基脲作用效果的理解。在本研究中，研究了2-吡啶甲醛硫代氨基脲（PCT）及其铜配合物（PCT-Cu）对细胞增殖的抑制作用。铜螯合物的抗肿瘤活性提高了3至10倍（IC50<5 μM）。结果表明，PCT和PCT-Cu在体外和体内均诱导活性氧（ROS）生成，导致细胞DNA片段化、线粒体膜去极化和细胞周期停滞。蛋白质印迹法显示PCT和PCT-Cu均诱导细胞凋亡。用这些试剂处理后，HepG2细胞中GRP78的上调表明发生了内质网（ER）应激。此外，本研究还揭示了钙释放，表明PCT和PCT-Cu扰乱了钙稳态。值得注意的是，PCT-Cu使毒胡萝卜素刺激的内质网钙释放敏感化，这与它们诱导的ROS水平相关，这意味着PCT和PCT-Cu的抗肿瘤活性部分源于钙动员，这种情况在少数研究中有报道。我们的发现可能有助于显著增进对硫代氨基脲衍生物的抗增殖作用及其抗肿瘤机制的理解。
