Evaluation of Polo-like Kinase 1 inhibition on the G2/M checkpoint in Acute Myelocytic Leukaemia.
Polo-Kinase 1 (PLK1) is a key cell cycle regulator that is necessary for checkpoint recovery after DNA damage-induced G2 arrest. We have examined the effects of PLK inhibition in Acute Myelocytic Leukaemia (AML) cells, whose resistance to genotoxic agents is thought to be associated with checkpoint reinforcement. We report that in U937 AML cells, PLK1 participates in checkpoint recovery, and that inhibition of PLK by the GW843682X compound results in mitotic accumulation and apoptosis. We also found that when challenged with VP-16, inhibition of PLK1 prevented U937 cells from checkpoint exit. Finally, we found that treatment with GW843682X slightly reduced genotoxic-induced inhibition of colony formation efficiency of primary leukaemia cells (CFU-L) from AML patients.
Didier
Christine
C
Institut d'Exploration Fonctionnelle des Génomes, University of Toulouse, 118 route de Narbonne, 31062 Toulouse, France.
Cavelier
Cindy
C
Quaranta
Muriel
M
Demur
Cécile
C
Ducommun
Bernard
B
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D020298:U937 Cells; D000097869:Polo-Like Kinase 1
D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D005047:Etoposide; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D000097869:Polo-Like Kinase 1; C524135:5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-((2-(trifluoromethyl)benzyl)oxy)thiophene-2-carboxamide