DITMD-induced mitotic defects and apoptosis in tumor cells by blocking the polo-box domain-dependent functions of polo-like kinase 1.
Eur J Pharmacol
; 847: 113-122, 2019 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-30689997
ABSTRACT
DITMD (1, 3- Dioxolo[4,5-g] isoquinolinium 5, 6, 7, 8- tetrahydro- 4- methoxy- 6, 6- dimethyl- 5- [2- oxo- 2- (2-pyridinyl)ethyl] - iodide) is a natural product-like compound with a hydrocotarnine moiety. The aim of this study was to investigate the anticancer effects of DITMD including mitotic arrest, apoptosis, radiosensitization, and to further explore its possible mechanism. DITMD (3-30⯵M) induced an obvious cell cycle delay at G2/M transition and apoptosis in HeLa cells. In a validation study, DITMD caused chromosome alignment defects and accumulation of mitotic markers such as polo-like kinase 1, cyclin B1, and phospho-histone H3. DITMD pre-treatment for 11â¯h also significantly decreased the cells' survival after X-ray irradiation. In mechanism studies, DITMD inhibited the polo-box domain of polo-like kinase 1 but not the conserved kinase domain. Molecular modeling also suggests that DITMD binds at the phosphate group recognition site and inhibits the action on phospho-peptide ligands. In addition, DITMD was analyzed as a PLHSpT competitive inhibitor with an IC50 value of 2.1⯵M and exhibited good selectivity against 105 distinct kinases. Taken together, these results indicate that DITMD induced chromosome alignment defects, apoptosis and radio-sensitization, and suggest that one mechanism underlying these anticancer effects involves inhibiting the polo-box domain-dependent functions of polo-like kinase 1.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas
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Proteínas Serina-Treonina Quinases
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Apoptose
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Proteínas de Ciclo Celular
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Inibidores de Proteínas Quinases
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Mitose
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article