CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner

Cyclin-dependent kinase 1 (CDK1) orchestrates the transition from the G2 phase into mitosis and as cancer cells often display enhanced CDK1 activity, it has been proposed as a tumor specific anti-cancer target. Here we show that the effects of CDK1 inhibition are not restricted to tumor cells but ca...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Cell cycle (Georgetown, Tex.) Ročník 17; číslo 12; s. 1513 - 1523
Hlavní autoři:	Prevo, Remko, Pirovano, Giacomo, Puliyadi, Rathi, Herbert, Katharine J., Rodriguez-Berriguete, Gonzalo, O'Docherty, Alice, Greaves, William, McKenna, W. Gillies, Higgins, Geoff S.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Taylor & Francis 18.06.2018
Témata:	CDC2 Protein Kinase - antagonists & inhibitors CDK1 (cyclin-dependent kinase) inhibitor cell cycle arrest Cell Division - drug effects Cell Line, Tumor Cell Proliferation - drug effects DNA Damage - drug effects epithelial cells fibroblasts G2 Phase - drug effects HeLa Cells Humans radiation Radiation-Sensitizing Agents - pharmacology radiosensitivity radiotherapy Research Paper RO-3306 Signal Transduction - drug effects fibroblasts radiation radiosensitivity radiotherapy RO-3306 epithelial cells CDK1 (cyclin-dependent kinase) inhibitor cell cycle arrest
ISSN:	1538-4101, 1551-4005, 1551-4005
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	Cyclin-dependent kinase 1 (CDK1) orchestrates the transition from the G2 phase into mitosis and as cancer cells often display enhanced CDK1 activity, it has been proposed as a tumor specific anti-cancer target. Here we show that the effects of CDK1 inhibition are not restricted to tumor cells but can also reduce viability in non-cancer cells and sensitize them to radiation in a cell cycle dependent manner. Radiosensitization by the specific CDK1 inhibitor, RO-3306, was determined by colony formation assays in three tumor lines (HeLa, T24, SQ20B) and three non-cancer lines (HFL1, MRC-5, RPE). Initial results showed that CDK1 inhibition radiosensitized tumor cells, but did not sensitize normal fibroblasts and epithelial cells in colony formation assays despite effective inhibition of CDK1 signaling. Further investigation showed that normal cells were less sensitive to CDK1 inhibition because they remained predominantly in G1 for a prolonged period when plated in colony formation assays. In contrast, inhibiting CDK1 a day after plating, when the cells were going through G2/M phase, reduced their clonogenic survival both with and without radiation. Our finding that inhibition of CDK1 can damage normal cells in a cell cycle dependent manner indicates that targeting CDK1 in cancer patients may lead to toxicity in normal proliferating cells. Furthermore, our finding that cell cycle progression becomes easily stalled in non-cancer cells under normal culture conditions has general implications for testing anti-cancer agents in these cells.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1538-4101 1551-4005 1551-4005
DOI:	10.1080/15384101.2018.1491236