The chemopreventive agents 4-HPR and DFMO inhibit growth and induce apoptosis in uterine leiomyomas.

Abstract

This study examined the effects of the chemopreventive agents 4-(N-hydroxyphenyl)retinamide (4-HPR) and alpha-difluoromethylornithine (DFMO) on leiomyoma growth. Primary cultures of human uterine leiomyomas and matched normal myometrium were established from hysterectomy specimens. After treatment with 4-HPR, DFMO, or the combination 4-HPR plus DFMO, cell growth was analyzed. Apoptosis was quantified with the use of a flow cytometric terminal deoxynucleotidyl transferase-mediated fluorescein-deoxyuridine-triphosphate nick-end labeling assay. Protein extracts were analyzed with Western blot for p53, p21, and p16. 4-HPR and DFMO inhibited the growth and induced apoptosis of leiomyoma cells, but not matched normal myometrial cells. Both 4-HPR and DFMO caused cells to accumulate at G0/G1, with a corresponding decrease in the S-phase fraction. Both agents also caused the induction of p53, p21, and p16. The chemopreventive agents 4-HPR and DFMO inhibit leiomyoma cell growth in vitro and induce apoptosis, which implies that retinoids and polyamines are important regulators of leiomyoma growth.