Activation of Caspase-3 in HL-60 Cells Treated with Pyrithione and Zinc

Kondoh, Masuo; Tasaki, Emi; Takiguchi, Mitsuyoshi; Higashimoto, Minoru; Watanabe, Yoshihisa; Sato, Masao

doi:10.1248/bpb.28.757

Cited by 16 publications

(9 citation statements)

References 19 publications

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“…1C and D, gray bars) and A549 cells (data not shown) under these conditions. The absence of cytotoxicity is in contrast to reports about proapoptotic activities of PT and HK in other cell lines such as HL-60 cells (15,19,20).…”

Section: Resultscontrasting

confidence: 99%

Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections

Krenn

Gaudernak

Holzer

et al. 2009

J Virol

141

124

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We have discovered two metal ion binding compounds, pyrithione (PT) and hinokitiol (HK), that efficiently inhibit human rhinovirus, coxsackievirus, and mengovirus multiplication. Early stages of virus infection are unaffected by these compounds. However, the cleavage of the cellular eukaryotic translation initiation factor eIF4GI by the rhinoviral 2A protease was abolished in the presence of PT and HK. We further show that these compounds inhibit picornavirus replication by interfering with proper processing of the viral polyprotein. In addition, we provide evidence that these structurally unrelated compounds lead to a rapid import of extracellular zinc ions into cells. Imported Zn 2؉ was found to be localized in punctate structures, as well as in mitochondria. The observed elevated level of zinc ions was reversible when the compounds were removed. As the antiviral activity of these compounds requires the continuous presence of the zinc ionophore PT, HK, or pyrrolidine-dithiocarbamate, the requirement for zinc ions for the antiviral activity is further substantiated. Therefore, an increase in intracellular zinc levels provides the basis for a new antipicornavirus mechanism.Curing virus infections harbors an enormous economic potential, and the search for new antiviral substances is of great interest for worldwide health. We have previously described the commonly used NF-B inhibitor and metal ion chelator pyrrolidine-dithiocarbamate (PDTC) to significantly inhibit the replication of several picornaviruses such as human rhinovirus (HRV), poliovirus, coxsackievirus, and mengovirus (9,22). These examples suggest that a common step in the life cycle of these picornaviruses is the target for the antiviral drug.In particular, we have demonstrated that PDTC has negative effects on picornavirus replication by influencing the processing of the viral polyprotein (21,22).The antiviral activity of PDTC is not restricted to the family Picornaviridae, since PDTC was shown to prevent the multiplication of human influenza virus, a member of the Orthomyxoviridae (33, 34). However, due to strong differences in the life cycle and host-cell interaction between human influenza virus and picornaviruses, it is likely that entirely different mechanisms might be relevant for the antiviral action of PDTC against these viruses.Currently, the precise mode of the antiviral action of PDTC is unknown, although several theories have been substantiated with experimental evidence. Antioxidative properties of PDTC are postulated to be the reason for antiviral effects against influenza virus infections (33), which is not the case for human rhinovirus multiplication (9).We have demonstrated that the antiviral effects of PDTC are metal ion dependent, and, in particular, Zn 2ϩ ions play a pivotal role. To underline the hypothesis that influx of zinc into the cells has antiviral capacity, pyrithione (PT) and hinokitiol (HK) were examined. PT is known to be a zinc ionophore that leads to a rapid increase in intracellular zinc levels (27), and HK is a ch...

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Section: Resultscontrasting

confidence: 99%

Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections

Krenn

Gaudernak

Holzer

et al. 2009

J Virol

141

124

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“…Its anticancer activity was first reported in the 1980s, though it was thought to be functioning as an iron chelator (35,36). When added to cells along with zinc it induced apoptosis (37)(38)(39). Although the sodium salt of pyrithione is water soluble, the zinc salt is not, prompting the synthesis and description of several water soluble derivatives designed to be used as anticancer drugs (23).…”

Section: Recognition That Some Metal-binding Compounds Act As Ionophomentioning

confidence: 99%

Metal ionophores – An emerging class of anticancer drugs

2009

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SummaryCompounds that bind metals such as copper and zinc have many biological activities, including the ability to induce apoptosis in cancer cells. Although some of these compounds have been considered to act as chelators of metals, decreasing their bioavailability, others increase intracellular metal concentrations. We review recent work regarding the recognition of the biological effects of metal ionophores with different structures, particularly with regard to their actions upon cancer cells focusing on dithiocarbamates, pyrithione, and the 8-hydroxyquinoline derivative, clioquinol. We provide a biologically based classification of metal-binding compounds that allows an experimental distinction between chelators and ionophores that can be readily used by biologists, which may lead to further study and classification of metal-binding drugs. Metal ionophores may kill cancer cells by a number of mechanisms, including lysosomal disruption and proteasome inhibition, and likely others. Because some of these compounds have been safely administered to animals and humans, they have the potential to become clinically useful anticancer agents.

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“…In allergic asthma, the loss of airway epithelial zinc was accompanied by changes in the expression of caspase-3 and apoptosis (30,31). Treatment of HL-60 cells with zinc chelators increases apoptosis via activation of caspase-3 (32). The small molecule procaspase-3 activator PAC-1 releases procaspase-3 from zinc-mediated inhibition (33)(34)(35).…”

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confidence: 99%

Zinc-mediated Allosteric Inhibition of Caspase-6

Velázquez-Delgado

Hardy

2012

Journal of Biological Chemistry

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Background: Caspase-6 is a critical factor in neurodegeneration, which is regulated by zinc binding. Results: Caspase-6 is inhibited by zinc and binds one zinc/monomer at an exosite distal from the active site. Conclusion: Zinc allosterically inhibits caspase-6 by locking it into a naturally occurring, inactive, and extended helical conformation. Significance: The allosteric inhibition observed in the presence of zinc may aid in the development of allosteric caspase-6 drugs.

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Activation of Caspase-3 in HL-60 Cells Treated with Pyrithione and Zinc

Cited by 16 publications

References 19 publications

Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections

Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections

Metal ionophores – An emerging class of anticancer drugs

Zinc-mediated Allosteric Inhibition of Caspase-6

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