Limits...
Identification of Novel Small Organic Compounds with Diverse Structures for the Induction of Epstein-Barr Virus (EBV) Lytic Cycle in EBV-Positive Epithelial Malignancies.

Choi CK, Ho DN, Hui KF, Kao RY, Chiang AK - PLoS ONE (2015)

Bottom Line: Five hit compounds were selected after three successive rounds of increasingly stringent screening.They neither cause hyperacetylation of histone proteins nor significant PKC activation at their working concentrations, suggesting that their biological mode of action are distinct from that of the known chemical inducers.One of the two compounds bears structural resemblance to iron chelators and the other strongly activates the MAPK pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

ABSTRACT
Phorbol esters, which are protein kinase C (PKC) activators, and histone deacetylase (HDAC) inhibitors, which cause enhanced acetylation of cellular proteins, are the main classes of chemical inducers of Epstein-Barr virus (EBV) lytic cycle in latently EBV-infected cells acting through the PKC pathway. Chemical inducers which induce EBV lytic cycle through alternative cellular pathways may aid in defining the mechanisms leading to lytic cycle reactivation and improve cells' responsiveness towards lytic induction. We performed a phenotypic screening on a chemical library of 50,240 novel small organic compounds to identify novel class(es) of strong inducer(s) of EBV lytic cycle in gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Five hit compounds were selected after three successive rounds of increasingly stringent screening. All five compounds are structurally diverse from each other and distinct from phorbol esters or HDAC inhibitors. They neither cause hyperacetylation of histone proteins nor significant PKC activation at their working concentrations, suggesting that their biological mode of action are distinct from that of the known chemical inducers. Two of the five compounds with rapid lytic-inducing action were further studied for their mechanisms of induction of EBV lytic cycle. Unlike HDAC inhibitors, lytic induction by both compounds was not inhibited by rottlerin, a specific inhibitor of PKCĪ“. Interestingly, both compounds could cooperate with HDAC inhibitors to enhance EBV lytic cycle induction in EBV-positive epithelial cancer cells, paving way for the development of strategies to increase cells' responsiveness towards lytic reactivation. One of the two compounds bears structural resemblance to iron chelators and the other strongly activates the MAPK pathways. These structurally diverse novel organic compounds may represent potential new classes of chemicals that can be used to investigate any alternative mechanism(s) leading to EBV lytic cycle reactivation from latency.

Show MeSH

Related in: MedlinePlus

Structures of iron chelators with structural similarity to C7.(a) The structure of the iron chelator 2-pyridylcarboxaldehyde isonicotyinoyl hydrazone (PCIH) and its analogues. (b) The structure of 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH), the iron chelator in the PCIH series in which C7 is most structurally similar to. (c) The structure of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), a well-known iron chelator.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4696655&req=5

pone.0145994.g007: Structures of iron chelators with structural similarity to C7.(a) The structure of the iron chelator 2-pyridylcarboxaldehyde isonicotyinoyl hydrazone (PCIH) and its analogues. (b) The structure of 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH), the iron chelator in the PCIH series in which C7 is most structurally similar to. (c) The structure of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), a well-known iron chelator.

Mentions: Owing to the ability of C7 to reactivate EBV lytic cycle in all the cell lines tested, we investigated in greater detail if its structure displays similarity to any groups of known compounds or drugs. The hydrazone bridge of C7 is a common structural entity among synthetic iron chelators, e.g. 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) and its analogs [58], and very similar to the well-known iron chelator di-2-pyridylketone-4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) (Fig 7A and 7C). Among them, compound C7 bears the greatest resemblance to the 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH) (Fig 7B). It is very likely that C7 also possess iron-binding or iron-chelating capabilities like PCBBH and Dp44mT. As iron chelators have not been previously reported in research studies to induce EBV lytic cycle in EBV-associated epithelial cancers, we reckon that further investigation into this would open up a possibility to a new large class of chemicals that induce EBV lytic cycle in EBV latently-infected cells.


Identification of Novel Small Organic Compounds with Diverse Structures for the Induction of Epstein-Barr Virus (EBV) Lytic Cycle in EBV-Positive Epithelial Malignancies.

Choi CK, Ho DN, Hui KF, Kao RY, Chiang AK - PLoS ONE (2015)

Structures of iron chelators with structural similarity to C7.(a) The structure of the iron chelator 2-pyridylcarboxaldehyde isonicotyinoyl hydrazone (PCIH) and its analogues. (b) The structure of 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH), the iron chelator in the PCIH series in which C7 is most structurally similar to. (c) The structure of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), a well-known iron chelator.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696655&req=5

pone.0145994.g007: Structures of iron chelators with structural similarity to C7.(a) The structure of the iron chelator 2-pyridylcarboxaldehyde isonicotyinoyl hydrazone (PCIH) and its analogues. (b) The structure of 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH), the iron chelator in the PCIH series in which C7 is most structurally similar to. (c) The structure of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), a well-known iron chelator.
Mentions: Owing to the ability of C7 to reactivate EBV lytic cycle in all the cell lines tested, we investigated in greater detail if its structure displays similarity to any groups of known compounds or drugs. The hydrazone bridge of C7 is a common structural entity among synthetic iron chelators, e.g. 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) and its analogs [58], and very similar to the well-known iron chelator di-2-pyridylketone-4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) (Fig 7A and 7C). Among them, compound C7 bears the greatest resemblance to the 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH) (Fig 7B). It is very likely that C7 also possess iron-binding or iron-chelating capabilities like PCBBH and Dp44mT. As iron chelators have not been previously reported in research studies to induce EBV lytic cycle in EBV-associated epithelial cancers, we reckon that further investigation into this would open up a possibility to a new large class of chemicals that induce EBV lytic cycle in EBV latently-infected cells.

Bottom Line: Five hit compounds were selected after three successive rounds of increasingly stringent screening.They neither cause hyperacetylation of histone proteins nor significant PKC activation at their working concentrations, suggesting that their biological mode of action are distinct from that of the known chemical inducers.One of the two compounds bears structural resemblance to iron chelators and the other strongly activates the MAPK pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

ABSTRACT
Phorbol esters, which are protein kinase C (PKC) activators, and histone deacetylase (HDAC) inhibitors, which cause enhanced acetylation of cellular proteins, are the main classes of chemical inducers of Epstein-Barr virus (EBV) lytic cycle in latently EBV-infected cells acting through the PKC pathway. Chemical inducers which induce EBV lytic cycle through alternative cellular pathways may aid in defining the mechanisms leading to lytic cycle reactivation and improve cells' responsiveness towards lytic induction. We performed a phenotypic screening on a chemical library of 50,240 novel small organic compounds to identify novel class(es) of strong inducer(s) of EBV lytic cycle in gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Five hit compounds were selected after three successive rounds of increasingly stringent screening. All five compounds are structurally diverse from each other and distinct from phorbol esters or HDAC inhibitors. They neither cause hyperacetylation of histone proteins nor significant PKC activation at their working concentrations, suggesting that their biological mode of action are distinct from that of the known chemical inducers. Two of the five compounds with rapid lytic-inducing action were further studied for their mechanisms of induction of EBV lytic cycle. Unlike HDAC inhibitors, lytic induction by both compounds was not inhibited by rottlerin, a specific inhibitor of PKCĪ“. Interestingly, both compounds could cooperate with HDAC inhibitors to enhance EBV lytic cycle induction in EBV-positive epithelial cancer cells, paving way for the development of strategies to increase cells' responsiveness towards lytic reactivation. One of the two compounds bears structural resemblance to iron chelators and the other strongly activates the MAPK pathways. These structurally diverse novel organic compounds may represent potential new classes of chemicals that can be used to investigate any alternative mechanism(s) leading to EBV lytic cycle reactivation from latency.

Show MeSH
Related in: MedlinePlus