title: Calcium release induced by 2-pyridinecarboxaldehyde thiosemicarbazone and its copper complex contributes to tumor cell death.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Youxun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Sufeng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Pingxin
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003300:Copper / Q000737:chemistry*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D011725:Pyridines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; C522921:picolinaldehyde; D003300:Copper; D002118:Calcium