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1.
Cancer Pathog Ther ; 1(2): 111-115, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37750087

RESUMO

Carrimycin is a synthetic macrolide antibiotic that has been shown to have anti-cancer activity; however, its exact mechanism of action and molecular target were previously unknown. It was recently elucidated that Isovalerylspiramycin I (ISP I), the active component of carrimycin, targets selenoprotein H (SelH), a nucleolar reactive oxygen species-scavenging enzyme in the selenoprotein family. ISP I treatment accelerates SelH degradation, resulting in oxidative stress, disrupted ribosomal biogenesis, and apoptosis in tumor cells. Specifically, ISP I disrupts the association between RNA polymerase I and ribosomal DNA in the nucleolus. This inhibits ribosomal RNA transcription and subsequent ribosomal assembly, which prevents cancer cells from sustaining elevated rates of protein synthesis and cellular proliferation that are necessary for tumor growth and malignancy. In this review, we (1) describe the historical categorization and evolution of anti-cancer agents, including macrolide antibiotics, (2) outline the discovery of SelH as a target of ISP I, and (3) summarize the ways in which carrimycin has been used both clinically and at the bench to date and propose additional potential therapeutic uses.

2.
Nat Commun ; 12(1): 3448, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103496

RESUMO

Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.


Assuntos
Replicação do DNA , Origem de Replicação , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Ciclopentanos/farmacologia , Replicação do DNA/efeitos dos fármacos , Replicação do DNA/genética , Genoma Humano , Humanos , Mitose/efeitos dos fármacos , Modelos Biológicos , Pirimidinas/farmacologia , Origem de Replicação/genética
3.
Aging (Albany NY) ; 11(11): 3585-3600, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31170091

RESUMO

Elevated expression of lncRNA H19 (H19) in the setting of hypoxia has been implicated as a promising therapeutic target for various cancers. However, little is known about the impact and underlying mechanism of H19 in ischemic brain stroke. This study found that H19 levels were elevated in the serum of stroke patients, as well as in the ischemic penumbra of rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and neuronal cells with oxygen glucose deprivation (OGD). Further, knockdown of H19 with siRNA alleviated cell apoptosis in OGD neuronal cells, and inhibition of H19 in MCAO/R rats significantly decreased neurological deficit, brain infarct volume and neuronal apoptosis. Lastly, with gain and loss of function studies, dual luciferase reported assay, RNA immunoprecipitation (RIP) and pull-down experiments, we demonstrated the dual competitive interaction of miR-19a with H19 and the 3'-UTR of Id2 mRNA, resulting in the identification of the H19-miR-19a-Id2 axis. With biological studies, we also revealed that H19-miR-19a-Id2 axis modulated hypoxia induced neuronal apoptosis. This study demonstrates that the identified H19-miR-19a-Id2 axis plays a critical role in hypoxia induced neuronal apoptosis, and blocking this axis may serve as a novel therapeutic strategy for ischemic brain injury.


Assuntos
Hipóxia-Isquemia Encefálica/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , Acidente Vascular Cerebral/metabolismo , Idoso , Animais , Apoptose/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Hipóxia-Isquemia Encefálica/sangue , Hipóxia-Isquemia Encefálica/genética , Proteína 2 Inibidora de Diferenciação/genética , Proteína 2 Inibidora de Diferenciação/metabolismo , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Neurônios/patologia , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , RNA Interferente Pequeno , Ratos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética
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