Taxol and anti-stathmin therapy: a synergistic combination that targets the mitotic spindle.
Stathmin is an abundant cytosolic phosphoprotein that plays an important role in the regulation of cellular proliferation. Its major function is to promote depolymerization of the microtubules that make up the mitotic spindle. Taxol is an effective chemotherapeutic agent whose activity is mediated through stabilization of the microtubules of the mitotic spindle. We demonstrate that antisense inhibition of stathmin expression chemosensitizes K562 leukemic cells to the antitumor effects of Taxol and results in a synergistic inhibition of their growth and clonogenic potential. In the presence of stathmin inhibition, exposure to Taxol results in more severe mitotic abnormalities (hypodiploidy and multinucleation). This, in turn, results in increased apoptosis of the aneuploid cells during subsequent cell division cycles. This novel molecular-based therapeutic approach may provide an effective form of cancer therapy that would avoid the severe toxicities associated with the use of multiple chemotherapeutic agents with overlapping toxicity profiles.
Iancu
C
C
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Mistry
S J
SJ
Arkin
S
S
Atweh
G F
GF
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D005472:Fluorouracil / Q000633:toxicity; D006801:Humans; D020014:K562 Cells; D008868:Microtubule Proteins; D020319:Oligodeoxyribonucleotides, Antisense / Q000633:toxicity*; D017239:Paclitaxel / Q000633:toxicity*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects*; D050777:Stathmin; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014410:Tumor Stem Cell Assay
D008868:Microtubule Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D010750:Phosphoproteins; D011994:Recombinant Proteins; C493995:STMN1 protein, human; D050777:Stathmin; D004317:Doxorubicin; D013762:Tetrahydrofolate Dehydrogenase; D017239:Paclitaxel; D005472:Fluorouracil