TY - JOUR

T1 - GF-15, a Novel Inhibitor of Centrosomal Clustering, Suppresses Tumor Cell Growth In Vitro and In Vivo

A1 - Raab,Marc S.

A1 - Breitkreutz,Iris

A1 - Anderhub,Simon

A1 - Rønnest,Mads Holger

A1 - Leber,Blanka

A1 - Larsen,Thomas Ostenfeld

A1 - Weiz,Ludmila

A1 - Konotop,Gleb

A1 - Hayden,Patrick J.

A1 - Podar,Klaus

A1 - Fruehauf,Johannes

A1 - Nissen,Felix

A1 - Mier,Walter

A1 - Haberkorn,Uwe

A1 - Ho,Anthony D.

A1 - Goldschmidt,Hartmut

A1 - Anderson,Kenneth C.

A1 - Clausen,Mads Hartvig

A1 - Krämer,Alwin

AU - Raab,Marc S.

AU - Breitkreutz,Iris

AU - Anderhub,Simon

AU - Rønnest,Mads Holger

AU - Leber,Blanka

AU - Larsen,Thomas Ostenfeld

AU - Weiz,Ludmila

AU - Konotop,Gleb

AU - Hayden,Patrick J.

AU - Podar,Klaus

AU - Fruehauf,Johannes

AU - Nissen,Felix

AU - Mier,Walter

AU - Haberkorn,Uwe

AU - Ho,Anthony D.

AU - Goldschmidt,Hartmut

AU - Anderson,Kenneth C.

AU - Clausen,Mads Hartvig

AU - Krämer,Alwin

PB - American Association for Cancer Research (A A C R)

PY - 2012

Y1 - 2012

N2 - In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells with supernumerary centrosomes to undergo multipolar mitoses resulting in apoptotic cell death. Here, we describe the characterization of the novel small molecule GF-15, a derivative of griseofulvin, as a potent inhibitor of centrosomal clustering in malignant cells. At concentrations where GF-15 had no significant impact on tubulin polymerization, spindle tension was markedly reduced in mitotic cells upon exposure to GF-15. Moreover, isogenic cells with conditional centrosome amplification were more sensitive to GF-15 than parental controls. In a wide array of tumor cell lines, mean inhibitory concentrations (IC50) for proliferation and survival were in the range of 1 to 5 μmol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro and in vivo antitumor efficacy of a prototype small molecule inhibitor of centrosomal clustering and strongly support the further evaluation of this new class of molecules. Cancer Res; 72(20); 5374–85. ©2012 AACR.

AB - In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells with supernumerary centrosomes to undergo multipolar mitoses resulting in apoptotic cell death. Here, we describe the characterization of the novel small molecule GF-15, a derivative of griseofulvin, as a potent inhibitor of centrosomal clustering in malignant cells. At concentrations where GF-15 had no significant impact on tubulin polymerization, spindle tension was markedly reduced in mitotic cells upon exposure to GF-15. Moreover, isogenic cells with conditional centrosome amplification were more sensitive to GF-15 than parental controls. In a wide array of tumor cell lines, mean inhibitory concentrations (IC50) for proliferation and survival were in the range of 1 to 5 μmol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro and in vivo antitumor efficacy of a prototype small molecule inhibitor of centrosomal clustering and strongly support the further evaluation of this new class of molecules. Cancer Res; 72(20); 5374–85. ©2012 AACR.

U2 - 10.1158/0008-5472.CAN-12-2026

DO - 10.1158/0008-5472.CAN-12-2026

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 20

VL - 72

SP - 5374

EP - 5385

ER -