title: Promising anti-leukemic activity of atorvastatin.
abstract: There is a current need for novel therapeutic strategies for the treatment of chronic lymphocytic leukemia (CLL), a still incurable hematological cancer involving mainly deregulated apoptosis. The purpose of the present study was to determine ex vivo the effect of the synthetic statin, atorvastatin, a known cholesterol-lowering drug, on peripheral blood mononuclear cells obtained from CLL patients. Using flow cytometry, we investigated the viability and induction of apoptosis in leukemic cells exposed to statin by the Vybrant apoptosis assay kit #4, compared with untreated control cells. We also examined the expression levels of apoptosis-regulatory proteins (Mcl-1, Bcl-2 and Bax), as well as products of the expression/proteolysis of lamin B, poly(ADP-ribose) polymerase‑1 (PARP‑1) and p27Kip1 by western blot analysis. Moreover, the number of sub-G1 cells and DNA fragmentation in atorvastatin-treated leukemic cells were examined by flow cytometry and agarose gel electrophoresis, respectively. The obtained results indicated that CLL cells ex vivo were extremely sensitive to atorvastatin. The cytotoxic effect of this statin was caused by the induction of apoptosis in the leukemic cells. The induction of apoptosis in the drug-treated model cells was confirmed by the reduction or proteolysis of apoptotic markers, such as PARP-1, lamin B and p27Kip1, the increase in the number of sub-G1 cells and DNA ladder formation. During atorvastatin-triggered apoptosis, changes in the expression levels of mitochondrial outer membrane permeability regulatory proteins of the Bcl-2 family were also observed. Ex vivo promising data indicate the strong cytotoxic and pro-apoptotic potential of atorvastatin against leukemic cells, but not normal cells. The obtained data suggest that atorvastatin be considered as a therapeutic option for the treatment of CLL.
authors: Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Łódź, 90-236 Łódź, Poland.
authors: Jolanta D
authors: JD
authors: Żołnierczyk
authors: Arleta
authors: A
authors: Borowiak
authors: Paweł
authors: P
authors: Hikisz
authors: Barbara
authors: B
authors: Cebula-Obrzut
authors: Jerzy Z
authors: JZ
authors: Błoński
authors: Piotr
authors: P
authors: Smolewski
authors: Tadeusz
authors: T
authors: Robak
authors: Zofia M
authors: ZM
authors: Kiliańska
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000069059:Atorvastatin; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097682:Lamin B Receptor
chemical_list: D051017:Apoptosis Regulatory Proteins; D000069059:Atorvastatin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006538:Heptanoic Acids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D018160:Receptors, Cytoplasmic and Nuclear; D051028:bcl-2-Associated X Protein; D000097682:Lamin B Receptor; C436291:CDKN1B protein, human; C579095:MCL1 protein, human; C499320:PARP1 protein, human