The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells.
OBJECTIVE
To investigate the effects of the antifibrotic drug halofuginone on extracellular matrix production, cell proliferation, and apoptosis of cultured myometrial and leiomyoma smooth muscle cells.


METHODS
Comparative and controlled experimental research study.


METHODS
University research laboratory.


METHODS
Leiomyoma and myometrial tissues were obtained from eight different patients at the time of elective hysterectomy.


METHODS
The effects of halofuginone on cell proliferation were assessed by tritiated thymidine uptake assays and cell count assays. Effects on TGFbeta1, collagen type I, and collagen type III mRNA levels were assessed by quantitative real-time polymerase chain reaction. Effects on apoptosis were assayed using a chemiluminescent assay to measure changes in caspase 3 and 7.


RESULTS
Halofuginone inhibited cell proliferation of both leiomyoma and autologous myometrial cells in a dose-dependent manner by inhibiting DNA synthesis within 24 hours and later inducing apoptosis (as measured by increased caspase 3/7) by 48-72 hours. Halofuginone also significantly reduced collagen type I (alpha1) and collagen type III (alpha1) mRNA levels, as well as the profibrotic factor TGFbeta1 mRNA levels in both cell types.


CONCLUSIONS
These results provide evidence to support the use of the antifibrotic drug halofuginone as a novel drug treatment for uterine leiomyomas.
Grudzien
Meagan M
MM
Department of Animal Sciences, University of Illinois, Urbana, Illinois, USA.
Low
Philip Steven
PS
Manning
Peter C
PC
Arredondo
Melissa
M
Belton
Robert J
RJ
Nowak
Romana A
RA
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D024061:Collagen Type III / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005260:Female; D005355:Fibrosis; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D009215:Myometrium / Q000187:drug effects* / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000473:pathology
D024042:Collagen Type I; D024061:Collagen Type III; D006131:Growth Inhibitors; D010880:Piperidines; D052999:Quinazolinones; D016212:Transforming Growth Factor beta; C010176:halofuginone