Synergistic growth inhibitory effects of interferon-alpha and lovastatin on bcr-abl positive leukemic cells.
The chimeric bcr-abl tyrosine kinase is of crucial pathogenic importance in chronic myeloid leukemia (CML). As shown, bcr-abl activates the ras pathway by phosphorylation of adapter proteins such as Grb-2 and Crkl. Functional inhibition of p21ras might partially inhibit the mitogenic signaling by bcr-abl. By depletion of cellular mevalonate pools, p21ras proteins can be rendered non-functional as a result of deficient post-translational protein farnesylation. We investigated the pharmacologic effect of mevalonate depletion by lovastatin in conjunction with interferon-alpha 2b (INF-alpha 2b) in bcr-abl positive K562 cells. At various concentrations, both drugs synergistically reduced cell proliferation of CML line K562 in a liquid culture system as well as clonal growth of colony forming units in a patient with newly diagnosed CML. Lovastatin and IFN-alpha 2b in combination led to cell cycle arrest and resulted in significant reduction of phosphorylation on tyrosine, serine, and threonine protein residues. IFN-alpha 2b alone showed little effect on protein phosphorylation but strongly enhanced lovastatin driven loss of phosphorylation. Subsequently, DNA fragmentation occurred in 50% of cells. In conclusion, exposure to IFN-alpha 2b and lovastatin synergistically inhibited proliferation of bcr-abl positive cells and resulted in loss of protein phosphorylation and subsequent apoptosis in K562 cells. Our in vitro model suggests further investigations are required of the potential value of HMG-CoA reductase inhibitors as adjunct to therapy of CML with interferon.
Müller-Tidow
Carsten
C
Department of Medicine, Hematology/Oncology, University of Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany. muellerc@uni-muenster.de
Kiehl
Michael
M
Sindermann
Jürgen R
JR
Probst
Michael
M
Banger
Nicola
N
Zühlsdorf
Michael
M
Chou
Ting-Chao
TC
Berdel
Wolfgang E
WE
Serve
Hubert
H
Koch
Olaf M
OM
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism*; D008148:Lovastatin / Q000627:therapeutic use*; D008798:Mevalonic Acid / Q000378:metabolism; D010766:Phosphorylation; D017368:Protein Prenylation; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011994:Recombinant Proteins; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013912:Threonine; D014443:Tyrosine; D012694:Serine; D008148:Lovastatin; D016044:Fusion Proteins, bcr-abl; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D008798:Mevalonic Acid