A Review of the Anti-Fibroid Potential of Medicinal Plants: Mechanisms and Targeted Signaling Pathways doi.org/10.26538/tjnpr/v5i5.1
Main Article Content
Abstract
Uterine fibroid or leiomyoma is the most common gynecological disorder affecting women. Treatment of symptomatic fibroids to date has been surgical, consisting of total abdominal hysterectomy or myomectomy. To decrease surgery’s impact, patients are progressively looking for uterus-protecting, negligibly obtrusive therapies/prevention for asymptomatic/symptomatic uterine fibroids. Medicinal plants/herbs and their active phytoconstituents have been used for the therapy of fibroids and associated uterine complications. Therefore this review highlights mechanisms by which phytochemicals modulate fibroid growth pathways. To achieve this aim, we performed a systematic search within the two largest medical-related scientific databases, PubMed and SCOPUS. We considered all papers representing original research and reporting specific phytochemicals used in the studies. Of the 227 papers identified, only twenty-six of these met the required considerations: 80.77% in vitro, 15.39% in vivo, and 3.84% in silico. The most studied plants and phytoconstituents used in treatment/prevention to inhibit fibroid growth/proliferation pathways were: Scutellaria barbata D. Don, Curcuma longa L. (Turmeric), and resveratrol, curcumin, and anthocyanins, respectively. Also, the main pathways of target for fibroid inhibition were cell-cycle arrest, apoptosis through an increase in ROS above cell viability thresh-hold, and inhibition of ECM proteins via reduction of growth factors. This review highlights natural anti-fibroid phytoextracts and the pharmacological mechanism by which they modulate fibroid pathways, thus providing key insights to developing new and innovative therapeutic options for the management of symptoms in women with uterine fibroids.
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References
Giuliani E, As-Sanie S, Marsh EE. Epidemiology and management of uterine fibroids. Int J Gynaecol Obstet. 2020; 149(1):3-9.
Donnez J and Dolmans MM. Uterine fibroid management: From the present to the future. Hum Reprod Update. 2016;22(6):665-686.
Khan AT, Shehmar M, Gupta JK. Uterine fibroids: Current perspectives. Int J Womens Health. 2014; 6:95-114.
Dvorska D, Brany D, Dankova Z, Halasova E, Visnovsky J. Molecular and clinical attributes of uterine leiomyomas. Tumour Biol. 2017; 39(6):1010428317710226.
Ukaonu CB. Prevalence and sonographic patterns of uterine fibroid among women of reproductive age in Jos, Plateau state, Nigeria. Radiol. 2017.
Ukwenya V, Maduemezia N, Afolayan O, Alese O, Thomas W. Prevalence of uterine fibroid in a south-western Nigerian population: A sonographic study. JECA. 2015; 14(1):24.
Fasubaa OB, Sowemimo OO, Ayegbusi OE, Abdur-Rahim ZF, Idowu BS, Ayobami O, Babalola OE, Akindojutimi AJ. Contributions of uterine fibroids to infertility at Ile‑ife, south‑western Nigeria. Trop J Obstet Gynaecol. 2018; 35(3):266-270.
Ozumba B, Nzegwu M, Anyikam A. Histological patterns of gynaecological lesions in Enugu, Nigeria. A five-year review from January 1, 2000 to December 31st 2004. Adv Biores. 2011; 2:132-136.
Eduwem D, Akintomide A, Bassey D, Ekott M. Hysterosalpingographic patterns and relevance in the management of infertility in a Nigerian tertiary health institution. Asian J Med Sci. 2016; 7(5):70-74.
Stewart EA, Laughlin-Tommaso SK, Catherino WH, Lalitkumar S, Gupta D, Vollenhoven B. Uterine fibroids. Nat Rev Dis Primers. 2016; 2(1):16043.
Ikhena DE and Bulun SE. Literature review on the role of uterine fibroids in endometrial function. Reprod Sci. 2018; 25(5):635-643.
Hoffman SR, Vines AI, Halladay JR, Pfaff E, Schiff L, Westreich D, Sundaresan A, Johnson L-S, Nicholson WK. Optimizing research in symptomatic uterine fibroids with development of a computable phenotype for use with electronic health records. Am J Obstet Gynecol. 2018;218(6):610.
Baranov VS, Osinovskaya NS, Yarmolinskaya MI. Pathogenomics of uterine fibroids development. Int J Mol Sci. 2019; 20(24):6151.
Botía C, Camarasa S, Baixauli F, Sanchez A. Uterine fibroids: Understanding their origins to better understand their future treatments. J Tumor Res. 2017; 3(130):2.
Medikare V, Kandukuri LR, Ananthapur V, Deenadayal M, Nallari P. The genetic bases of uterine fibroids; a review. J Reprod Infertil. 2011; 12(3):181-191.
Yarmolinskaya MI, Polenov NI, Kunitsa VV. Uterine fibroids: The role of signaling pathways in the pathogenesis. A literature review. J Obstet and Women's Dis. 2020; 69(5):113-124.
Islam MS, Segars JH, Castellucci M, Ciarmela P. Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target. Pharmacol Rep. 2017; 69(1):57-70.
Borahay MA, Al-Hendy A, Kilic GS, Boehning D. Signaling pathways in leiomyoma: Understanding pathobiology and implications for therapy. Mol Med. 2015; 21(1):242-256.
Borahay MA, Asoglu MR, Mas A, Adam S, Kilic GS, AlHendy A. Estrogen receptors and signaling in fibroids: Role in pathobiology and therapeutic implications. Reprod Sci. 2017; 24(9):1235-1244.
Pavone D, Clemenza S, Sorbi F, Fambrini M, Petraglia F. Epidemiology and risk factors of uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2018;46:3-11.
Sparic R, Mirkovic L, Malvasi A, Tinelli A. Epidemiology of uterine myomas: A review. Int J Fertil Steril. 2016; 9(4):424-435.
Soave I and Marci R. From obesity to uterine fibroids: Anintricate network. Curr Med Res Opin. 2018; 34(11):1877-1879.
Tak YJ, Lee SY, Park SK, Kim YJ, Lee JG, Jeong DW, Kim SC, Kim IJ, Yi YH. Association between uterine leiomyoma and metabolic syndrome in parous premenopausal women: A case–control study. Med. 2016; 95(46).
Uimari O, Auvinen J, Jokelainen J, Puukka K, Ruokonen A, Jarvelin MR, Piltonen T, Keinanen-Kiukaanniemi S, Zondervan K, Jarvela I, Ryynanen M, Martikainen H. Uterine fibroids and cardiovascular risk. Hum Reprod. 2016; 31(12):2689-2703.
Sabry M and Al-Hendy A. Medical treatment of uterine leiomyoma. Reprod Sci. 2012; 19(4):339-353.
Bonine NG, Banks E, Harrington A, Vlahiotis A, Moore-Schiltz L, Gillard P. Contemporary treatment utilization among women diagnosed with symptomatic uterine fibroids in the united states. BMC women's health. 2020; 20(1):1-13.
Lewis TD, Malik M, Britten J, San Pablo AM, Catherino WH. A comprehensive review of the pharmacologic management of uterine leiomyoma. Biomed Res Int. 2018; 2018:2414609.
Ali M and Al-Hendy A. Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids. Biol Reprod. 2017; 97(3):337-352.
Metwally M, Raybould G, Cheong YC, Horne AW. Surgical treatment of fibroids for subfertility. Cochrane Database Syst Rev. 2020; 1(1):CD003857.
Mas A, Tarazona M, Dasi Carrasco J, Estaca G, Cristobal I, Monleon J. Updated approaches for management of uterine fibroids. Int J Womens Health. 2017;9:607-617.
Chittawar PB, Franik S, Pouwer AW, Farquhar C. Minimally invasive surgical techniques versus open myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2014(10).
Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014; 12:CD005073.
Wang Y, Zhang S, Li C, Li B, Ouyang L. Minimally invasive surgery for uterine fibroids. Ginekol Pol. 2020; 91(3):149-157.
Nezhat C, Vang N, Vu M, Grossman J, Skinner J, Robinson K, Saini K, Vaid A, Maule L, Adler JR. A novel approach for treatment of uterine fibroids: Stereotactic radiosurgery as a proposed treatment modality. Curr Obstet Gynecol Rep. 2020:1-6.
Taylor DK and Leppert PC. Treatment for uterine fibroids: Searching for effective drug therapies. Drug Discov Today Ther Strateg. 2012; 9(1):e41-e49.
Sohn GS, Cho S, Kim YM, Cho CH, Kim MR, Lee SR, Working Group of Society of Uterine L. Current medical treatment of uterine fibroids. Obstet Gynecol Sci. 2018; 61(2):192-201.
Ciebiera M, Ali M, Prince L, Jackson-Bey T, Atabiekov I, Zgliczynski S, Al-Hendy A. The evolving role of natural compounds in the medical treatment of uterine fibroids. J Clin Med. 2020; 9(5):1479.
Veeresham C. Natural products derived from plants as a source of drugs. J Adv Pharm Technol Res. 2012; 3(4):200.
Islam MS, Akhtar MM, Ciavattini A, Giannubilo SR, Protic O, Janjusevic M, Procopio AD, Segars JH, Castellucci M, Ciarmela P. Use of dietary phytochemicals to target inflammation, fibrosis, proliferation, and angiogenesis in uterine tissues: Promising options for prevention and treatment of uterine fibroids? Mol Nutr Food Res. 2014; 58(8):1667-1684.
Sahin K, Ozercan R, Onderci M, Sahin N, Khachik F, Seren S, Kucuk O. Dietary tomato powder supplementation in the prevention of leiomyoma of the oviduct in the Japanese quail. Nutr Cancer. 2007; 59(1):70-75.
Wong TF, Takeda T, Li B, Tsuiji K, Kondo A, Tadakawa M, Nagase S, Yaegashi N. Curcumin targets the akt-mtor pathway for uterine leiomyosarcoma tumor growth suppression. Int J Clin Oncol. 2014; 19(2):354-363.
Yu CH, Zhao JS, Zhao H, Peng T, Shen DC, Xu QX, Li Y, Webb RC, Wang MH, Shi XM, Peng C, Ding WJ. Transcriptional profiling of uterine leiomyoma rats treated by a traditional herb pair, curcumae rhizoma and sparganii rhizoma. Braz J Med Biol Res. 2019; 52(6):e8132.
Ju Y and Xiao B. Chemical constituents of cyperus rotundus l. And their inhibitory effects on uterine fibroids. Afr J Med Health Sci. 2016; 16(4):1000-1006.
Wong TF, Takeda T, Li B, Tsuiji K, Kitamura M, Kondo A, Yaegashi N. Curcumin disrupts uterine leiomyosarcoma cells through akt-mtor pathway inhibition. Gynecol Oncol. 2011; 122(1):141-148.
Islam MS, Giampieri F, Janjusevic M, Gasparrini M, ForbesHernandez TY, Mazzoni L, Greco S, Giannubilo SR, Ciavattini A, Mezzetti B. An anthocyanin rich strawberry extract induces apoptosis and ros while decreases glycolysis and fibrosis in human uterine leiomyoma cells. Oncotarget. 2017; 8(14):23575.
Giampieri F, Islam MS, Greco S, Gasparrini M, Forbes Hernandez TY, Delli Carpini G, Giannubilo SR, Ciavattini A, Mezzetti B, Mazzoni L, Capocasa F, Castellucci M, Battino M, Ciarmela P. Romina: A powerful strawberry with in vitro efficacy against uterine leiomyoma cells. J Cell Physiol. 2019; 234(5):7622-7633.
Lee TK, Kim DI, Song YL, Lee YC, Kim HM, Kim CH. Differential inhibition of scutellaria barbata d. Don (lamiaceae) on hcg-promoted proliferation of cultured uterine leiomyomal and myometrial smooth muscle cells. Immunopharmacol Immunotoxicol. 2004; 26(3):329-342.
Lee TK, Lee YJ, Kim DI, Kim HM, Chang YC, Kim CH. Pharmacological activity in growth inhibition and apoptosis of cultured human leiomyomal cells of tropical plant scutellaria barbata d. Don (lamiaceae). Environ Toxicol Pharmacol. 2006; 21(1):70-79.
Kim D-I, Lee T-K, Lim I-S, Kim H, Lee Y-C, Kim C-H. Regulation of igf-i production and proliferation of human leiomyomal smooth muscle cells by scutellaria barbata d. Don in vitro: Isolation of flavonoids of apigenin and luteolin as acting compounds. Toxicol Appl Pharmacol. 2005; 205(3):213-224.
Kim KW, Jin UH, Kim DI, Lee TK, Kim MS, Oh MJ, Kim MS, Kwon DY, Lee YC, Kim CH. Antiproliferative effect of scutellaria barbata d. Don. On cultured human uterine leiomyoma cells by down-regulation of the expression of Bcl-2 protein. Phytother Res. 2008; 22(5):583-590.
Chen HY, Lin PH, Shih YH, Wang KL, Hong YH, Shieh TM, Huang TC, Hsia SM. Natural antioxidant resveratrol suppresses uterine fibroid cell growth and extracellular matrix formation in vitro and in vivo. Antioxidants (Basel). 2019; 8(4):99.
Wu C-H, Shieh T-M, Wei L-H, Cheng T-F, Chen H-Y, Huang T-C, Wang K-L, Hsia S-M. Resveratrol inhibits proliferation of
myometrial and leiomyoma cells and decreases extracellularmatrix-associated protein expression. J Funct Foods. 2016; 23:241-252.
Ciarmela P, Islam MS, Reis FM, Gray PC, Bloise E, Petraglia F, Vale W, Castellucci M. Growth factors and myometrium: Biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update. 2011; 17(6):772-790.
Segars JH, Parrott EC, Nagel JD, Guo XC, Gao X, Birnbaum LS, Pinn VW, Dixon D. Proceedings from the third national institutes of health international congress on advances in uterine leiomyoma research: Comprehensive review, conference summary and future recommendations. Hum Reprod Update. 2014; 20(3):309-333.
Rates SMK. Plants as source of drugs. Toxicon. 2001;39(5):603-613.
Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A. Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertil Steril. 2010; 94(5):1887-1893.
Roshdy E, Rajaratnam V, Maitra S, Sabry M, Allah AS, AlHendy A. Treatment of symptomatic uterine fibroids with green tea extract: A pilot randomized controlled clinical study. Int J Womens Health. 2013; 5:477-486.
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.
Redza-Dutordoir M and Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta. 2016; 1863(12):2977-2992.
Fletcher NM, Saed MG, Abu-Soud HM, Al-Hendy A, Diamond MP, Saed GM. Uterine fibroids are characterized by an impaired antioxidant cellular system: Potential role of hypoxia in the pathophysiology of uterine fibroids. J Assist Reprod Genet. 2013;30(7):969-974.
Fletcher NM, Abusamaan MS, Memaj I, Saed MG, Al-Hendy A, Diamond MP, Saed GM. Oxidative stress: A key regulator of leiomyoma cell survival. Fertil Steril. 2017; 107(6):1387-1394 e1381.
Asare GA, Akuffo G, Doku D, Asiedu B, Santa S. Dynamics of urinary oxidative stress biomarkers: 8-hydroxy-2'-deoxyguanosine and 8-isoprostane in uterine leiomyomas. J Midlife Health. 2016; 7(1):8-14.
Kim SJ, Kim HS, Seo YR. Understanding of ros-inducing strategy in anticancer therapy. Oxid Med Cell Longev. 2019; 2019:5381692.
Raza MH, Siraj S, Arshad A, Waheed U, Aldakheel F, Alduraywish S, Arshad M. Ros-modulated therapeutic approaches in cancer treatment. J Cancer Res Clin Oncol. 2017; 143(9):1789-1809.
Gibson SB. Investigating the role of reactive oxygen species in regulating autophagy. Methods in enzymology. 528: Elsevier; 2013; 217-235p.
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C,
Boya P, Brenner C, Campanella M, Candi E, CarmonaGutierrez D, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, DeBerardinis RJ, Deshmukh M, Di Daniele N, Di Virgilio F, Dixit VM, Dixon SJ, Duckett CS, Dynlacht BD, El-Deiry WS, Elrod JW, Fimia GM, Fulda S, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Golstein P, Gottlieb E, Green DR, Greene LA, Gronemeyer H, Gross A, Hajnoczky G, Hardwick JM, Harris IS, Hengartner MO, Hetz C, Ichijo H, Jaattela M, Joseph B, Jost PJ, Juin PP, Kaiser WJ, Karin M, Kaufmann T, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Knight RA, Kumar S, Lee SW, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, Lopez-Otin C, Lowe SW, Luedde T, Lugli E, MacFarlane M, Madeo F, Malewicz M, Malorni W, Manic G, Marine JC, Martin SJ, Martinou JC, Medema JP, Mehlen P,
Meier P, Melino S, Miao EA, Molkentin JD, Moll UM, MunozPinedo C, Nagata S, Nunez G, Oberst A, Oren M, Overholtzer
M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pereira DM, Pervaiz S, Peter ME, Piacentini M, Pinton P, Prehn JHM, Puthalakath H, Rabinovich GA, Rehm M, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Ryan KM, Sayan E, Scorrano L, Shao F, Shi Y, Silke J, Simon HU, Sistigu A, Stockwell BR, Strasser A, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Thorburn A, Tsujimoto Y, Turk B, Vanden Berghe T, Vandenabeele P, Vander Heiden MG, Villunger A, Virgin HW, Vousden KH, Vucic D, Wagner EF, Walczak H, Wallach D, Wang Y, Wells JA, Wood W, Yuan J, Zakeri Z, Zhivotovsky B, Zitvogel L, Melino G, Kroemer G. Molecular mechanisms of cell death: Recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018; 25(3):486-541.
Jan R and Chaudhry GE. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull. 2019;
(2):205-218.
Cho YS. The role of necroptosis in the treatment of diseases. BMB Rep. 2018; 51(5):219-224.
Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: Cell survival and cell death. Int J Cell Biol. 2010;2010:214074.
Flusberg DA and Sorger PK. Surviving apoptosis: Life-deathsignaling in single cells. Trends Cell Biol. 2015; 25(8):446-458.
Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ. 2015;22(4):526-539.
Yue J and Lopez JM. Understanding MAPK signaling pathwaysin apoptosis. Int J Mol Sci. 2020; 21(7):2346.
Csatlos E, Mate S, Laky M, Rigo J, Jr., Joo JG. Role of apoptosis in the development of uterine leiomyoma: Analysis of expression patterns of BCL-2 and BAX in human leiomyoma tissue with clinical correlations. Int J Gynecol Pathol. 2015; 34(4):334-339.
Naseri MH, Mahdavi M, Davoodi J, Tackallou SH, Goudarzvand M, Neishabouri SH. Up regulation of BAX and down regulation of bcl2 during 3-NC mediated apoptosis in human cancer cells. Cancer Cell Int. 2015; 15(1):55.
Wu HL, Chuang TY, Al-Hendy A, Diamond MP, Azziz R, Chen YH. Berberine inhibits the proliferation of human uterine leiomyoma cells. Fertil Steril. 2015; 103(4):1098-1106.
Kim C-H, Kim D-I, Kwon C-N, Kang S-K, Jin U-H, Suh S-J, Lee T-K, Lee I-S. Euonymus alatus (thunb.) sieb induces apoptosis via mitochondrial pathway as prooxidant in human uterine leiomyomal smooth muscle cells. Int J Gynecol Cancer. 2006; 16(2).
Lee J-W, Choi HJ, Kim E-J, Hwang WY, Jung M-H, Kim KS. Fisetin induces apoptosis in uterine leiomyomas through multiple pathways. Sci Rep. 2020; 10(1):1-12.
Eskander RN, Randall LM, Sakai T, Guo Y, Hoang B, Zi X. Flavokawain b, a novel, naturally occurring chalcone, exhibits robust apoptotic effects and induces g2/m arrest of a uterine leiomyosarcoma cell line. J Obstet Gynaecol Res. 2012; 38(8):1086-1094.
Lee SM, Choi ES, Ha E, Ji KY, Shin SJ, Jung J. Gyejibongnyeong-hwan (gui zhi fu ling wan) ameliorates human uterine myomas via apoptosis. Front Pharmacol. 2019;10:1105.
Pauzi N, Mohd KS, Abdul Halim NH, Ismail Z. Orthosiphon stamineus extracts inhibits proliferation and induces apoptosis in uterine fibroid cells. Asian Pac J Cancer Prev. 2018; 19(10):2737-2744.
Zakaria N, Mohd KS, Ahmed Saeed MA, Ahmed Hassan LE, Shafaei A, Al-Suede FSR, Memon AH, Ismail Z. Anti-uterine fibroid effect of standardized labisia pumila var. Alata extracts in vitro and in human uterine fibroid cancer xenograft model. Asian Pac J Cancer Prev. 2020; 21(4):943-951.
Banfalvi G. Overview of cell synchronization. Cell cycle synchronization: Springer; 2017; 3-27p.
Koç A, Wheeler LJ, Mathews CK, Merrill GF. Hydroxyurea arrests DNA replication by a mechanism that preserves basal dntp pools. J. Biol. Chem. 2004;279(1):223-230.
Purcell M, Kruger A, Tainsky MA. Gene expression profiling of replicative and induced senescence. Cell Cycle. 2014; 13(24):3927-3937.
Ahmed RS, Liu G, Renzetti A, Farshi P, Yang H, Soave C, Saed G, El-Ghoneimy AA, El-Banna HA, Foldes R, Chan TH, Dou QP. Biological and mechanistic characterization of novel prodrugs of green tea polyphenol epigallocatechin gallate analogs in human leiomyoma cell lines. J Cell Biochem. 2016; 117(10):2357-2369.
Porcaro G, Santamaria A, Giordano D, Angelozzi P. Vitamin dplus epigallocatechin gallate: A novel promising approach for uterine myomas. Eur Rev Med Pharmacol Sci. 2020; 24(6):3344-3351.
Prince TL, Lang BJ, Guerrero-Gimenez ME, Fernandez-Munoz JM, Ackerman A, Calderwood SK. Hsf1: Primary factor in molecular chaperone expression and a major contributor to cancer morbidity. Cells. 2020; 9(4):1046.
Dai C. The heat-shock, or hsf1-mediated proteotoxic stress, response in cancer: From proteomic stability to oncogenesis. Philos Trans R Soc Lond B Biol Sci. 2018; 373(1738):20160525.
Xia W, Voellmy R, Spector NL. Sensitization of tumor cells to fas killing through overexpression of heat‐shock transcription
factor 1. J Cell Physiol. 2000; 183(3):425-431.
Vilaboa N, Bore A, Martin-Saavedra F, Bayford M, Winfield N, Firth-Clark S, Kirton SB, Voellmy R. New inhibitor targeting human transcription factor hsf1: Effects on the heat shock response and tumor cell survival. Nucl Acids Res. 2017; 45(10):5797-5817.
Carpenter RL and Gökmen-Polar Y. Hsf1 as a cancer biomarker and therapeutic target. Curr Cancer Drug Targets. 2019; 19(7):515-524.
Khandagale P, Thakur S, Acharya N. Identification of PCNAinteracting protein motifs in human DNA polymerase delta. Biosci Rep. 2020; 40(4).
Boehm EM, Gildenberg MS, Washington MT. The many roles of PCNA in eukaryotic DNA replication. Enzym. 2016; 39:231-254.
Mailand N, Gibbs-Seymour I, Bekker-Jensen S. Regulation of PCNA-protein interactions for genome stability. Nat Rev Mol Cell Biol. 2013; 14(5):269-282.
Choe KN and Moldovan G-L. Forging ahead through darkness: PCNA, still the principal conductor at the replication fork. Mol cell. 2017; 65(3):380-392.
Strzalka W and Ziemienowicz A. Proliferating cell nuclear antigen (PCNA): A key factor in DNA replication and cell cycle regulation. Ann Bot. 2011; 107(7):1127-1140.
Jamaluddin MFB, Nahar P, Tanwar PS. Proteomic characterization of the extracellular matrix of human uterine fibroids. Endocrinology. 2018;159(7):2656-2669.
Islam MS, Ciavattini A, Petraglia F, Castellucci M, Ciarmela P. Extracellular matrix in uterine leiomyoma pathogenesis: A potential target for future therapeutics. Hum Reprod Update. 2018; 24(1):59-85.
Ko YA, Jamaluddin MFB, Adebayo M, Bajwa P, Scott RJ, Dharmarajan AM, Nahar P, Tanwar PS. Extracellular matrix (ecm) activates beta-catenin signaling in uterine fibroids. Reprod. 2018; 155(1):61-71.
Greco S, Islam MS, Zannotti A, Delli Carpini G, Giannubilo SR, Ciavattini A, Petraglia F, Ciarmela P. Quercetin and indole- 3-carbinol inhibit extracellular matrix expression in human primary uterine leiomyoma cells. Reprod Biomed Online. 2020; 40(4):593-602.
Lin PH, Shih CK, Yen YT, Chiang W, Hsia SM. Adlay (coix lachryma-jobi l. Var. Ma-yuen stapf.) hull extract and active compounds inhibit proliferation of primary human leiomyoma cells and protect against sexual hormone-induced mice smooth muscle hyperproliferation. Molecules. 2019; 24(8):1556.
Liberti MV, Locasale JW. The warburg effect: How does it benefit cancer cells? Trends Biochem Sci. 2016; 41(3):211-218.
Belisario DC, Kopecka J, Pasino M, Akman M, De Smaele E, Donadelli M, Riganti C. Hypoxia dictates metabolic rewiring of tumors: Implications for chemoresistance. Cells. 2020; 9(12):2598.
Ke X, Dou F, Cheng Z, Dai H, Zhang W, Qu X, Ding P, Zuo X. High expression of cyclooxygenase-2 in uterine fibroids and its correlation with cell proliferation. Eur J Obstet Gynecol Reprod Biol. 2013; 168(2):199-203.
Szweda M, Rychlik A, Babińska I, Pomianowski A. Cyclooxygenase-2 as a biomarker with diagnostic, therapeutic, prognostic, and predictive relevance in small animal oncology. J Vet Res. 2020; 64(1):151.
Zeng L, Yang K, Liu H, Zhang G. A network pharmacology approach to investigate the pharmacological effects of guizhi fuling wan on uterine fibroids. Exp Ther Med. 2017; 14(5):4697-4710.
Lee JH, Dean M, Austin JR, Burdette JE, Murphy BT. Irilone from red clover ( trifolium pratense) potentiates progesterone signaling. J Nat Prod. 2018; 81(9):1962-1967.