Faezeh Koohestani1, Wenan Qiang2, Amy L MacNeill3, Stacy A Druschitz4, Vanida A Serna5, Malavika Adur6, Takeshi Kurita5, Romana A Nowak7. 1. Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA Present address: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA. 2. Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA Department of Pathology, Northwestern University, Chicago, IL 60611, USA Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. 3. Department of Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana, IL 61801, USA Present address: Department of Microbiology, Immunology and Pathology, Colorado State University, Ft. Collins, CO 80523, USA. 4. Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA. 5. Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA Present address: Department of Molecular & Cellular Biochemistry, The Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. 6. Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA. 7. Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA ranowak@illinois.edu.
Abstract
STUDY QUESTION: Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model? SUMMARY ANSWER: HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis. WHAT IS KNOWN ALREADY: Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas. STUDY DESIGN, SIZE, DURATION: Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF. MAIN RESULTS AND THE ROLE OF CHANCE: Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P < 0.05) reduction in tumor volume. The HF-induced volume reduction was accompanied by increased apoptosis and decreased cell proliferation. In contrast, there was no significant change in the collagen content either at the transcript or protein level between UL xenografts in control and HF groups. HF treatment did not change the expression level of ovarian steroid hormone receptors. No adverse pathological effects were observed in other tissues from mice undergoing treatment at these doses. LIMITATIONS, REASONS FOR CAUTION: While this study did test the effects of HF on human leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery. STUDY FUNDING/COMPETING INTERESTS: This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests.
STUDY QUESTION: Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model? SUMMARY ANSWER: HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis. WHAT IS KNOWN ALREADY: Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of humanleiomyomas. STUDY DESIGN, SIZE, DURATION: Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group. PARTICIPANTS/MATERIALS, SETTING, METHODS:Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF. MAIN RESULTS AND THE ROLE OF CHANCE: Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P < 0.05) reduction in tumor volume. The HF-induced volume reduction was accompanied by increased apoptosis and decreased cell proliferation. In contrast, there was no significant change in the collagen content either at the transcript or protein level between UL xenografts in control and HF groups. HF treatment did not change the expression level of ovarian steroid hormone receptors. No adverse pathological effects were observed in other tissues from mice undergoing treatment at these doses. LIMITATIONS, REASONS FOR CAUTION: While this study did test the effects of HF on humanleiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery. STUDY FUNDING/COMPETING INTERESTS: This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests.
Authors: Daniel J Haisenleder; Aleisha H Schoenfelder; Elizabeth S Marcinko; Lisa M Geddis; John C Marshall Journal: Endocrinology Date: 2011-09-20 Impact factor: 4.736
Authors: Henry B Koon; Barbara Fingleton; Jeannette Y Lee; Julia T Geyer; Ethel Cesarman; Robert A Parise; Merrill J Egorin; Bruce J Dezube; David Aboulafia; Susan E Krown Journal: J Acquir Immune Defic Syndr Date: 2011-01-01 Impact factor: 3.731