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.

Growth Inhibition of a Novel Iron Chelator, DpdtC, against Hepatoma Carcinoma Cell Lines Partly Attributed to Ferritinophagy‐Mediated Lysosomal ROS Generation

“…Next, the ferric would be reduced by the reducing agents, which triggered Fenton reaction, producing massive ROS that caused an alteration in LMP. To test the hypothesis, LysoTracker Red that can accumulate within lysosomes was employed to assess the lysosome membrane permeability [ 13 ]. As shown in Figure 8 , the red fluorescence intensities of HepG2 cells were increased with treatment of DpdtC compared to nontreatment of the cells, indicating that more LysoTracker Red accumulated in lysosomes and LMP was altered ( Figure 8(b) ).…”

“…A cancer cell has higher iron demand than normal cell; reduction of iron availability will be a favor to inhibit cancer cell proliferation. One of the mechanisms of iron chelators is a disturbance of iron homeostasis [ 13 – 17 ], in addition, iron chelators can also induce apoptosis, autophagy, and inactivate ribonucleotide reductase. Therefore, iron chelation has been considered as a promising strategy in cancer therapy.…”

The novel dithiocarbamate, DpdtC suppresses HER2-overexpressed cancer cells by up-regulating NDRG1 via inactivation of HER2-ERK 1/2 signaling

“…Metal chelators are promising therapeutic agents that show marked and selective anti-tumor activity 1 , 2 . As we know, cancer cells have an increased demand for iron and copper to maintain proper cell growth rate; therefore, the use of chelators for cancer treatment has been an potential option 3 , 4 . The iron chelators such as di-2-pyridyl ketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and desferrioxamine (DFO) have shown pronounced inhibitory effects in several types of cancer 5 , 6 .…”

“…NDRG1 belongs to the NDRG (N-myc downstream-regulated gene) family which has been reported to function as a tumor and metastasis suppressor gene in several types of cancer including breast, pancreatic and prostate cancers 9 – 12 . Studies have shown that iron and copper chelators exhibited their anti-tumor effects through up-regulating NDRG1 level to regress tumor growth and suppress metastasis 4 , 13 , 14 . Moreover, chelators such as those of the dipyridyl thiosemicarbazone (DpT) class also exerted their metastasis-suppressive effects through up-regulating NDRG1 15 , 16 .…”

Síntese E Caracterização De Potenciais Metal-Protein Attenuating Compounds Hidrazônicos E Avaliação Da Complexação Ao Íon Vanadila Como Possível Forma De Administração No Contexto Da Doença De Alzheimer

“…Este composto também apresenta uma grande habilidade em se coordenar com vários íons metálicos de interesse biológico através dos átomos de nitrogênio piridínico, nitrogênio azometínico e oxigênio carbonílico. A 2-piridinacarboxaldeído, um dos precursores do 2PCAFUR, é reportada na literatura possuindo atividade anticâncer (Qi et al, 2017), antitumoral (Fu et al, 2017), antibacteriana, catalítica e ainda é empregada como material fotoativo (Ali et al, 2015). Além disso, a hidrazona formada a partir deste precursor atua como agente quelante em doenças relacionadas ao excesso de ferro (Richardson e Ponka, 1998;Richardson et al, 1999;Richardson, 2003;Richardson et al, 2006).…”