ABSTRACT
To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/metabolism , Cyclin-Dependent Kinases/metabolism , Microtubules/drug effects , Nuclear Proteins/metabolism , Phosphoprotein Phosphatases/metabolism , Protein-Tyrosine Kinases/metabolism , Spindle Apparatus/drug effects , Spindle Apparatus/metabolism , Adult , CDC2 Protein Kinase , Cell Line, Tumor , HeLa Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Young AdultABSTRACT
A woman with mitral prosthesis, treated with amiodarone i.v. (500 mg in two boluses) for an atrial tachycardia, shows repeated episodes of torsade de pointes. Although there is a connection between the intensity of electro-physiological alterations due to the anti-arrhythmic therapy and pro-arrhythmic effects, there are cases in which the torsade de pointes seems to be associated with modest alterations of QT intervals or even without high plasma concentrations of drugs. In these cases a genetic predisposition for drug's metabolism alteration or greater sensibility of target organs is suggested.
