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Semin Reprod Med 2017; 35(06): 487-493
DOI: 10.1055/s-0037-1607268
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Mechanical Signaling and Extracellular Matrix in Uterine Fibroids

Saima Rafique
1   Department of Obstetrics and Gynecology, Howard University Hospital, Washington, District of Columbia
,
James H. Segars
2   Howard W. and Georgeanna Seegar Jones Laboratory of Reproductive Sciences and Women's Health Research, Department of Obstetrics and Gynecology, Johns Hopkins Medical University, Baltimore, Maryland
,
Phyllis C. Leppert
3   Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina
› Author Affiliations
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Publication History

Publication Date:
03 November 2017 (online)

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Abstract

Fibroids (uterine leiomyomas) are the most common benign tumors of the female reproductive tract. Steroid hormones, growth factors, and cytokines have long been implicated in fibroid growth; however, research suggests that changes in the extracellular matrix and mechanical signaling play a critical role in fibroid growth and differentiation. Studies have shown that growth of fibroids is related to the change in the volume and composition of extracellular matrix with increased deposition of abnormal collagen, glycoproteins, laminins, fibronectins, and an increased osmotic stress. These changes generate mechanical stress which is converted to chemical signals in the cells through mechanotransduction and eventually affects gene expression and protein synthesis. Current studies also suggest that mechanical signaling in fibroid cells is abnormal as evidenced by decreased apoptosis of abnormal cells and deposition of a stiff extracellular matrix promoting fibrosis. Understanding and defining these mechanisms could help design new therapies for the treatment of fibroids.

Keywords

fibroids - extracellular matrix - mechanical signaling - mechanotransduction
 

  • References

  • 1 Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 2003; 111 (08) 1037-1054
    CrossrefPubMedGoogle Scholar
  • 2 Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003; 188 (01) 100-107
    CrossrefPubMedGoogle Scholar
  • 3 Marshall LM, Spiegelman D, Barbieri RL. , et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 1997; 90 (06) 967-973
    CrossrefPubMedGoogle Scholar
  • 4 Wise LA, Laughlin-Tommaso SK. Epidemiology of uterine fibroids: from menarche to menopause. Clin Obstet Gynecol 2016; 59 (01) 2-24
    CrossrefPubMedGoogle Scholar
  • 5 Bartels CB, Cayton KC, Chuong FS. , et al. An evidence-based approach to the medical management of fibroids: a systematic review. Clin Obstet Gynecol 2016; 59 (01) 30-52
    CrossrefPubMedGoogle Scholar
  • 6 Moroni R, Vieira C, Ferriani R, Candido-Dos-Reis F, Brito L. Pharmacological treatment of uterine fibroids. Ann Med Health Sci Res 2014; 4 (Suppl. 03) S185-S192
    CrossrefPubMedGoogle Scholar
  • 7 Donnez J, Tatarchuk TF, Bouchard P. , et al; PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012; 366 (05) 409-420
    CrossrefPubMedGoogle Scholar
  • 8 West CP, Lumsden MA, Lawson S, Williamson J, Baird DT. Shrinkage of uterine fibroids during therapy with goserelin (Zoladex): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot. Fertil Steril 1987; 48 (01) 45-51
    PubMedGoogle Scholar
  • 9 Fujita M. [Histological and biochemical studies of collagen in human uterine leiomyomas]. Hokkaido Igaku Zasshi 1985; 60 (04) 602-615
    PubMedGoogle Scholar
  • 10 Leppert PC, Baginski T, Prupas C, Catherino WH, Pletcher S, Segars JH. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril 2004; 82 (Suppl. 03) 1182-1187
    CrossrefPubMedGoogle Scholar
  • 11 Ingber DE. Tensegrity and mechanotransduction. J Bodyw Mov Ther 2008; 12 (03) 198-200
    CrossrefPubMedGoogle Scholar
  • 12 Mammoto T, Ingber DE. Mechanical control of tissue and organ development. Development 2010; 137 (09) 1407-1420
    CrossrefPubMedGoogle Scholar
  • 13 Wang N, Butler JP, Ingber DE. Mechanotransduction across the cell surface and through the cytoskeleton. Science 1993; 260 (5111): 1124-1127
    CrossrefPubMedGoogle Scholar
  • 14 Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression?. J Theor Biol 1982; 99 (01) 31-68
    CrossrefPubMedGoogle Scholar
  • 15 Miyamoto S, Teramoto H, Coso OA. , et al. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol 1995; 131 (03) 791-805
    CrossrefPubMedGoogle Scholar
  • 16 Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110 (06) 673-687
    CrossrefPubMedGoogle Scholar
  • 17 Mammoto T, Mammoto A, Ingber DE. Mechanobiology and developmental control. Annu Rev Cell Dev Biol 2013; 29: 27-61
    CrossrefPubMedGoogle Scholar
  • 18 Paszek MJ, Zahir N, Johnson KR. , et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 2005; 8 (03) 241-254
    CrossrefPubMedGoogle Scholar
  • 19 Malik R, Lelkes PI, Cukierman E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol 2015; 33 (04) 230-236
    CrossrefPubMedGoogle Scholar
  • 20 Iwahashi M, Muragaki Y. Increased type I and V collagen expression in uterine leiomyomas during the menstrual cycle. Fertil Steril 2011; 95 (06) 2137-2139
    CrossrefPubMedGoogle Scholar
  • 21 Stewart EA, Friedman AJ, Peck K, Nowak RA. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab 1994; 79 (03) 900-906
    PubMedGoogle Scholar
  • 22 Berto AG, Oba SM, Michelacci YM, Sampaio LO. Galactosaminoglycans from normal myometrium and leiomyoma. Braz J Med Biol Res 2001; 34 (05) 633-637
    CrossrefPubMedGoogle Scholar
  • 23 Kresse H, Schönherr E. Proteoglycans of the extracellular matrix and growth control. J Cell Physiol 2001; 189 (03) 266-274
    CrossrefPubMedGoogle Scholar
  • 24 Sugahara K, Masuda M, Harada T, Yamashina I, de Waard P, Vliegenthart JF. Structural studies on sulfated oligosaccharides derived from the carbohydrate-protein linkage region of chondroitin sulfate proteoglycans of whale cartilage. Eur J Biochem 1991; 202 (03) 805-811
    CrossrefPubMedGoogle Scholar
  • 25 Schönherr E, Hausser H, Beavan L, Kresse H. Decorin-type I collagen interaction. Presence of separate core protein-binding domains. J Biol Chem 1995; 270 (15) 8877-8883
    CrossrefPubMedGoogle Scholar
  • 26 Scott JE, Orford CR. Dermatan sulphate-rich proteoglycan associates with rat tail-tendon collagen at the d band in the gap region. Biochem J 1981; 197 (01) 213-216
    CrossrefPubMedGoogle Scholar
  • 27 Riquelme C, Larrain J, Schonherr E, Henriquez JP, Kresse H, Brandan E. Antisense inhibition of decorin expression in myoblasts decreases cell responsiveness to transforming growth factor beta and accelerates skeletal muscle differentiation. J Biol Chem 2001; 276 (05) 3589-3596
    CrossrefPubMedGoogle Scholar
  • 28 Takeda U, Utani A, Wu J. , et al. Targeted disruption of dermatopontin causes abnormal collagen fibrillogenesis. J Invest Dermatol 2002; 119 (03) 678-683
    CrossrefPubMedGoogle Scholar
  • 29 Catherino WH, Leppert PC, Stenmark MH. , et al. Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids. Genes Chromosomes Cancer 2004; 40 (03) 204-217
    CrossrefPubMedGoogle Scholar
  • 30 Wight TN. Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol 2002; 14 (05) 617-623
    CrossrefPubMedGoogle Scholar
  • 31 Westergren-Thorsson G, Norman M, Björnsson S. , et al. Differential expressions of mRNA for proteoglycans, collagens and transforming growth factor-beta in the human cervix during pregnancy and involution. Biochim Biophys Acta 1998; 1406 (02) 203-213
    CrossrefPubMedGoogle Scholar
  • 32 Ricciardelli C, Quinn DI, Raymond WA. , et al. Elevated levels of peritumoral chondroitin sulfate are predictive of poor prognosis in patients treated by radical prostatectomy for early-stage prostate cancer. Cancer Res 1999; 59 (10) 2324-2328
    PubMedGoogle Scholar
  • 33 Norian JM, Malik M, Parker CY. , et al. Transforming growth factor beta3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas. Reprod Sci 2009; 16 (12) 1153-1164
    CrossrefPubMedGoogle Scholar
  • 34 Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990; 6: 597-641
    CrossrefPubMedGoogle Scholar
  • 35 Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007; 293 (03) L525-L534
    CrossrefPubMedGoogle Scholar
  • 36 Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006; 69 (02) 213-217
    CrossrefPubMedGoogle Scholar
  • 37 Lee BS, Nowak RA. Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta 3 (TGF beta 3) and altered responses to the antiproliferative effects of TGF beta. J Clin Endocrinol Metab 2001; 86 (02) 913-920
    PubMedGoogle Scholar
  • 38 Arici A, Sozen I. Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril 2000; 73 (05) 1006-1011
    CrossrefPubMedGoogle Scholar
  • 39 Malik M, Catherino WH. Novel method to characterize primary cultures of leiomyoma and myometrium with the use of confirmatory biomarker gene arrays. Fertil Steril 2007; 87 (05) 1166-1172
    CrossrefPubMedGoogle Scholar
  • 40 Wolańska M, Sobolewski K, Drozdzewicz M, Bańkowski E. Extracellular matrix components in uterine leiomyoma and their alteration during the tumour growth. Mol Cell Biochem 1998; 189 (1-2): 145-152
    CrossrefPubMedGoogle Scholar
  • 41 Cramer SF, Horiszny J, Patel A, Sigrist S. The relation of fibrous degeneration to menopausal status in small uterine leiomyomas with evidence for postmenopausal origin of seedling myomas. Mod Pathol 1996; 9 (07) 774-780
    PubMedGoogle Scholar
  • 42 Curry Jr TE, Osteen KG. The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 2003; 24 (04) 428-465
    CrossrefPubMedGoogle Scholar
  • 43 Joseph DS, Malik M, Nurudeen S, Catherino WH. Myometrial cells undergo fibrotic transformation under the influence of transforming growth factor beta-3. Fertil Steril 2010; 93 (05) 1500-1508
    CrossrefPubMedGoogle Scholar
  • 44 Ingber DE. Cellular mechanotransduction: putting all the pieces together again. FASEB J 2006; 20 (07) 811-827
    CrossrefPubMedGoogle Scholar
  • 45 Rogers R, Norian J, Malik M. , et al. Mechanical homeostasis is altered in uterine leiomyoma. Am J Obstet Gynecol 2008; 198 (04) 474.e1-474.e11
    CrossrefPubMedGoogle Scholar
  • 46 Burg MB, Ferraris JD, Dmitrieva NI. Cellular response to hyperosmotic stresses. Physiol Rev 2007; 87 (04) 1441-1474
    CrossrefPubMedGoogle Scholar
  • 47 López-Rodríguez C, Antos CL, Shelton JM. , et al. Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression. Proc Natl Acad Sci U S A 2004; 101 (08) 2392-2397
    CrossrefPubMedGoogle Scholar
  • 48 Burg MB, Kwon ED, Kültz D. Regulation of gene expression by hypertonicity. Annu Rev Physiol 1997; 59: 437-455
    CrossrefPubMedGoogle Scholar
  • 49 Garcia-Perez A, Burg MB. Renal medullary organic osmolytes. Physiol Rev 1991; 71 (04) 1081-1115
    CrossrefPubMedGoogle Scholar
  • 50 McCarthy-Keith DM, Malik M, Britten J, Segars J, Catherino WH. Gonadotropin-releasing hormone agonist increases expression of osmotic response genes in leiomyoma cells. Fertil Steril 2011; 95 (07) 2383-2387
    CrossrefPubMedGoogle Scholar
  • 51 Juliano RL. Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol 2002; 42: 283-323
    CrossrefPubMedGoogle Scholar
  • 52 Arao S, Masumoto A, Otsuki M. Beta1 integrins play an essential role in adhesion and invasion of pancreatic carcinoma cells. Pancreas 2000; 20 (02) 129-137
    CrossrefPubMedGoogle Scholar
  • 53 Zaidel-Bar R, Itzkovitz S, Ma'ayan A, Iyengar R, Geiger B. Functional atlas of the integrin adhesome. Nat Cell Biol 2007; 9 (08) 858-867
    CrossrefPubMedGoogle Scholar
  • 54 Malik M, Segars J, Catherino WH. Integrin β1 regulates leiomyoma cytoskeletal integrity and growth. Matrix Biol 2012; 31 (7-8): 389-397
    CrossrefPubMedGoogle Scholar
  • 55 Chen HM, Lin YH, Cheng YM, Wing LY, Tsai SJ. Overexpression of integrin-β1 in leiomyoma promotes cell spreading and proliferation. J Clin Endocrinol Metab 2013; 98 (05) E837-E846
    CrossrefPubMedGoogle Scholar
  • 56 Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 1992; 70 (03) 389-399
    CrossrefPubMedGoogle Scholar
  • 57 Wettschureck N, Offermanns S. Rho/Rho-kinase mediated signaling in physiology and pathophysiology. J Mol Med (Berl) 2002; 80 (10) 629-638
    CrossrefPubMedGoogle Scholar
  • 58 Engler A, Bacakova L, Newman C, Hategan A, Griffin M, Discher D. Substrate compliance versus ligand density in cell on gel responses. Biophys J 2004; 86 (1, Pt 1): 617-628
    CrossrefPubMedGoogle Scholar
  • 59 Norian JM, Owen CM, Taboas J. , et al. Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma. Matrix Biol 2012; 31 (01) 57-65
    CrossrefPubMedGoogle Scholar
  • 60 Miller BT, Rubino DM, Driggers PH. , et al. Expression of brx proto-oncogene in normal ovary and in epithelial ovarian neoplasms. Am J Obstet Gynecol 2000; 182 (02) 286-295
    CrossrefPubMedGoogle Scholar
  • 61 Carnegie GK, Means CK, Scott JD. A-kinase anchoring proteins: from protein complexes to physiology and disease. IUBMB Life 2009; 61 (04) 394-406
    CrossrefPubMedGoogle Scholar
  • 62 Paszek MJ, Weaver VM. The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia 2004; 9 (04) 325-342
    CrossrefPubMedGoogle Scholar
  • 63 Koohestani F, Braundmeier AG, Mahdian A, Seo J, Bi J, Nowak RA. Extracellular matrix collagen alters cell proliferation and cell cycle progression of human uterine leiomyoma smooth muscle cells. PLoS One 2013; 8 (09) e75844
    CrossrefPubMedGoogle Scholar
  • 64 Taylor DK, Leppert PC. Treatment for uterine fibroids: searching for effective drug therapies. Drug Discov Today Ther Strateg 2012; 9 (01) e41-e49
    PubMedGoogle Scholar
  • 65 Nakazawa M, Yoshimura T, Naito J, Azuma H. [Pharmacological properties of N-(3′,4′-dimethoxycinnamoyl) anthranilic acid (N-5′), a new anti-atopic agent. (4).--Anti-inflammatory activity of N-5′ (author's transl)]. Nippon Yakurigaku Zasshi 1978; 74 (04) 473-481
    CrossrefPubMedGoogle Scholar
  • 66 Yamada H, Tajima S, Nishikawa T, Murad S, Pinnell SR. Tranilast, a selective inhibitor of collagen synthesis in human skin fibroblasts. J Biochem 1994; 116 (04) 892-897
    CrossrefPubMedGoogle Scholar
  • 67 Darakhshan S, Pour AB. Tranilast: a review of its therapeutic applications. Pharmacol Res 2015; 91: 15-28
    CrossrefPubMedGoogle Scholar
  • 68 Rogosnitzky M, Danks R, Kardash E. Therapeutic potential of tranilast, an anti-allergy drug, in proliferative disorders. Anticancer Res 2012; 32 (07) 2471-2478
    PubMedGoogle Scholar
  • 69 Shime H, Kariya M, Orii A. , et al. Tranilast inhibits the proliferation of uterine leiomyoma cells in vitro through G1 arrest associated with the induction of p21(waf1) and p53. J Clin Endocrinol Metab 2002; 87 (12) 5610-5617
    CrossrefPubMedGoogle Scholar
  • 70 Islam MS, Protic O, Ciavattini A. , et al. Tranilast, an orally active antiallergic compound, inhibits extracellular matrix production in human uterine leiomyoma and myometrial cells. Fertil Steril 2014; 102 (02) 597-606
    CrossrefPubMedGoogle Scholar
  • 71 Chuang TD, Khorram O. Tranilast inhibits genes functionally involved in cell proliferation, fibrosis, and epigenetic regulation and epigenetically induces miR-29c expression in leiomyoma cells. Reprod Sci 2017; 24 (09) 1253-1263
    CrossrefPubMedGoogle Scholar
  • 72 Fukushima M, Nakamuta M, Kohjima M. , et al. Fasudil hydrochloride hydrate, a Rho-kinase (ROCK) inhibitor, suppresses collagen production and enhances collagenase activity in hepatic stellate cells. Liver Int 2005; 25 (04) 829-838
    CrossrefPubMedGoogle Scholar
  • 73 Guan R, Xu X, Chen M. , et al. Advances in the studies of roles of Rho/Rho-kinase in diseases and the development of its inhibitors. Eur J Med Chem 2013; 70: 613-622
    CrossrefPubMedGoogle Scholar
  • 74 Malik M, Britten J, Segars J, Catherino WH. Leiomyoma cells in 3-dimensional cultures demonstrate an attenuated response to fasudil, a rho-kinase inhibitor, when compared to 2-dimensional cultures. Reprod Sci 2014; 21 (09) 1126-1138
    CrossrefPubMedGoogle Scholar
  • 75 Jayes FL, Liu B, Moutos FT, Kuchibhatla M, Guilak F, Leppert PC. Loss of stiffness in collagen-rich uterine fibroids after digestion with purified collagenase Clostridium histolyticum. Am J Obstet Gynecol 2016; 215 (05) 596.e1-596.e8
    CrossrefPubMedGoogle Scholar
  • 76 Holzer LA, Holzer G. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N Engl J Med 2009; 361 (26) 2579 , author reply 2579–2580
    PubMedGoogle Scholar
  • 77 Honig SC. Intralesional collagenase in the treatment of Peyronie's disease. Ther Adv Urol 2014; 6 (02) 47-53
    CrossrefPubMedGoogle Scholar
  • 78 French MF, Mookhtiar KA, Van Wart HE. Limited proteolysis of type I collagen at hyperreactive sites by class I and II Clostridium histolyticum collagenases: complementary digestion patterns. Biochemistry 1987; 26 (03) 681-687
    CrossrefPubMedGoogle Scholar
  • 79 Brunengraber LN, Jayes FL, Leppert PC. Injectable Clostridium histolyticum collagenase as a potential treatment for uterine fibroids. Reprod Sci 2014; 21 (12) 1452-1459
    CrossrefPubMedGoogle Scholar
  • 80 Catherino WH, Malik M. Uterine leiomyomas express a molecular pattern that lowers retinoic acid exposure. Fertil Steril 2007; 87 (06) 1388-1398
    CrossrefPubMedGoogle Scholar
  • 81 Levy G, Malik M, Britten J, Gilden M, Segars J, Catherino WH. Liarozole inhibits transforming growth factor-β3--mediated extracellular matrix formation in human three-dimensional leiomyoma cultures. Fertil Steril 2014; 102 (01) 272-281.e2
    CrossrefPubMedGoogle Scholar
  • 82 Sabry M, Halder SK, Allah AS, Roshdy E, Rajaratnam V, Al-Hendy A. Serum vitamin D3 level inversely correlates with uterine fibroid volume in different ethnic groups: a cross-sectional observational study. Int J Womens Health 2013; 5: 93-100
    PubMedGoogle Scholar
  • 83 Baird DD, Hill MC, Schectman JM, Hollis BW. Vitamin d and the risk of uterine fibroids. Epidemiology 2013; 24 (03) 447-453
    CrossrefPubMedGoogle Scholar
  • 84 Ylikomi T, Laaksi I, Lou YR. , et al. Antiproliferative action of vitamin D. Vitam Horm 2002; 64: 357-406
    PubMedGoogle Scholar
  • 85 Halder SK, Goodwin JS, Al-Hendy A. 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 2011; 96 (04) E754-E762
    CrossrefPubMedGoogle Scholar
  • 86 Halder SK, Osteen KG, Al-Hendy A. 1,25-dihydroxyvitamin d3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells. Biol Reprod 2013; 89 (06) 150
    PubMedGoogle Scholar
  • 87 Pines M, Snyder D, Yarkoni S, Nagler A. Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma. Biol Blood Marrow Transplant 2003; 9 (07) 417-425
    CrossrefPubMedGoogle Scholar
  • 88 Nagler A, Firman N, Feferman R, Cotev S, Pines M, Shoshan S. Reduction in pulmonary fibrosis in vivo by halofuginone. Am J Respir Crit Care Med 1996; 154 (4, Pt 1): 1082-1086
    CrossrefPubMedGoogle Scholar
  • 89 Adegunsoye A, Strek ME. Therapeutic approach to adult fibrotic lung diseases. Chest 2016; 150 (06) 1371-1386
    CrossrefPubMedGoogle Scholar
  • 90 Lee BS, Margolin SB, Nowak RA. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production. J Clin Endocrinol Metab 1998; 83 (01) 219-223
    CrossrefPubMedGoogle Scholar
  • 91 Grudzien MM, Low PS, Manning PC, Arredondo M, Belton Jr RJ, Nowak RA. The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells. Fertil Steril 2010; 93 (04) 1290-1298
    CrossrefPubMedGoogle Scholar
  • 92 Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003; 23 (1A): 363-398
    PubMedGoogle Scholar
  • 93 Malik M, Mendoza M, Payson M, Catherino WH. Curcumin, a nutritional supplement with antineoplastic activity, enhances leiomyoma cell apoptosis and decreases fibronectin expression. Fertil Steril 2009; 91 (5, Suppl): 2177-2184
    CrossrefPubMedGoogle Scholar