Curcumin inhibits human leiomyoma xenograft tumor growth and induces dissolution of the extracellular matrix.

OBJECTIVE: To determine whether a curcumin-supplemented diet would prevent and/or treat uterine leiomyoma growth in our mouse xenograft model. DESIGN: Animal study. SETTING: Laboratory study. PATIENT(S): N/A. INTERVENTION(S): Curcumin-supplemented diet. MAIN OUTCOME MEASURE(S): Dietary intake, blood concentrations, tumor size, extracellular matrix protein concentrations, apoptosis markers. RESULT(S): We found that curcumin was well tolerated as a dietary supplement, free curcumin and its metabolites were detected in the serum, and exposure resulted in approximately 60% less leiomyoma xenograft growth as well as dissolution of the peripheral extracellular matrix architecture of the xenografts. The production of matrix proteins, including collagens, decreased, whereas the number of apoptotic cells in the xenografts increased. Additionally, when xenografts were placed in a uterine intramural location, we found a significantly increased apoptotic response to curcumin in the diet. CONCLUSION(S): Mice on a diet supplemented with curcumin could achieve serum concentrations sufficient to regulate human leiomyoma xenograft growth, and curcumin could play both preventive and curative roles in the treatment of uterine leiomyoma as an oral nutritional supplement.

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha.

OBJECTIVE: To characterize the method by which angiogenesis occurred in three-dimensional (3D) leiomyoma xenografts, and to assess the impact of hypoxia on two-dimensional (2D) and 3D myometrial and leiomyoma cells and leiomyoma xenografts in vivo. DESIGN: Laboratory study. SETTING: Academic research. PATIENT(S): Cell cultures from patient-matched myometrial and leiomyoma tissues. INTERVENTION(S): In vivo 3D leiomyoma xenografts from ovariectomized mice treated with gonadal hormones; myometrial and leiomyoma cells in 2D and 3D growth formats exposed to 1% oxygen. MAIN OUTCOME MEASURE(S): Protein expression. RESULT(S): Blood vessels in the xenograft estradiol group are identified with anti-mouse/anti-rat CD31/PECAM-1 antibody. Hormone-stimulated 3D leiomyoma xenografts stain positively for adrenomedullin (ADM). Myometrial cells exposed to 1% oxygen demonstrated an increase in hypoxia-inducible factor (HIF)-1α at 6 hours and a marked increase at 24 hours. Under normoxic conditions, leiomyoma cells at 6 hours show increased expression of HIF-1α, which is further increased at 24 hours. Leiomyoma cells under hypoxia demonstrated a 1.14-fold decrease in HIF-1α expression at 6 hours and no change at 24 hours. Hypoxic myometrium decreased the proangiogenic protein ADM expression at 6 hours and showed a >1.5-fold increase at 24 hours. Normoxic leiomyoma decrease ADM at 24 hours and showed a >1.5-fold increase at 24 hours of hypoxia. CONCLUSION(S): Hypoxia-induced HIF-1α expression facilitates angiogenesis in 3D xenografts in vivo by increasing the expression of the proangiogenic protein ADM. Angiogenesis contributes to the viability and extended survival of these xenografts. Furthermore, 2D myometrial and leiomyoma cells increase HIF-1α and ADM expression in vitro under hypoxic conditions.

Ulipristal Acetate Mediates Decreased Proteoglycan Expression Through Regulation of Nuclear Factor of Activated T-Cells (NFAT5).

Nuclear factor of activated T-cells (NFAT5) is a tissue specific, osmoadaptive transcription factor essential for the control of hydration homeostasis in mammalian cells. Nuclear factor of activated T-cells regulates osmolyte transporters aldo-keto reductase family 1 member B1 (AKR1B1) and solute carrier family 5 member 3 (SLC5A3) to maintain fluid equilibrium in cells. The osmotic potential of the extracellular matrix of leiomyomas is attributed to the role of proteoglycans. In leiomyoma cells, NFAT5 is overexpressed compared to myometrial cells. The selective progesterone receptor modulator, ulipristal acetate, has been reported to decrease the size of leiomyomas in clinical trials. When treated with ulipristal acetate, both patient leiomyoma tissue and leiomyoma cells grown in 3-dimensional cultures show a decrease in the expression of NFAT5 protein, solute transporters AKR1B1 and SLC5A3, and results in an associated decline in the expression of proteoglycans, versican, aggrecan, and brevican. In summary, ulipristal acetate induces changes in leiomyoma cell osmoregulation which result in a decrease in proteoglycan expression.