Oxidative stress: a key regulator of leiomyoma cell survival
Dichloroacetate modulates redox balance, thus protecting cells against anaerobic metabolism and associated oxidative stress. This may provide targets for therapeutic intervention in the treatment of profibrotic disorders, including uterine leiomyomas.
Volume 107, Issue 6, Pages 1387–1394.e1
Nicole M. Fletcher, Ph.D., Mohammed S. Abusamaan, M.D., Ira Memaj, B.S., Mohammed G. Saed, B.A., Ayman Al-Hendy, M.D., Ph.D., Michael P. Diamond, M.D., Ghassan M. Saed, Ph.D.
To determine the effects of attenuating oxidative stress with the use of dichloroacetate (DCA) on the expression of key redox enzymes myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) as well as on apoptosis.
Prospective experimental study.
University medical center.
Cells established from myometrium and uterine fibroid from the same patients.
Cells were exposed to normal (20% O2) or hypoxic (2% O2) conditions for 24 hours with or without DCA (20 μg/mL), a metabolic modulator that shifts anaerobic to aerobic metabolism.
Main Outcome Measure(s)
Nitrate/nitrite (iNOS activity indicator), iNOS, Bcl-2/Bax ratio, MPO, and caspase-3 activities and levels were determined by means of Greiss assay, real-time reverse-transcription polymerase chain reaction, and ELISA. Data were analyzed with the use of SPSS by means of one-way analysis of variance with Tukey post hoc analysis and independent t tests.
MPO, iNOS, and nitrate/nitrite expression were higher in leiomyoma than in myometrial cells, and they were further enhanced by hypoxia in myometrial cells. Treatment with the use of DCA decreased MPO, iNOS, and nitrate/nitrite levels and negated the effect of hypoxia in both types of cells. Leiomyoma cells showed less apoptosis, as indicated by both caspase-3 activity and the Bcl-2/Bax ratio, than myometrial cells. Hypoxia further decreased apoptosis in myometrial cells with no further effect on leiomyoma cells. Treatment with DCA resulted in increased apoptosis in both types of cells, even in the presence of hypoxia.
Shifting anaerobic to aerobic metabolism with the use of DCA resulted in an increase in apoptosis in leiomyoma cells and protected myometrial cells from the acquisition of the leiomyoma-like phenotype.