The Clinical and Experimental Research on the Treatment of Endometriosis with Thiostrepton

Author(s): Ping Jin*, Xiaofei Chen, Guiyuan Yu, Ziyang Li, Qingqing Zhang, Jian V. Zhang*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 3 , 2019

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Graphical Abstract:


Background/Objective: Forkhead Box M1 (FOXM1) is frequently activated in tumors. We studied the expression and the possible mechanism of FOXM1 and evaluated the effects of thiostrepton in an endometriotic rat model.

Methods and Material: This was a randomized study in a rat model of endometriosis. Fifty female Wistar rats were surgically induced with endometriosis. After 4 weeks of observation, twenty and thirty rats were randomly allocated to an ovariectomized (OVX) group and a treatment group, respectively. The OVX group was ovariectomized and randomly divided into an OVX-estrogen group and a control (OVX -oil) group. All rats were allowed a resting period of 3 days prior to any operation. The rats in the estrogen group were given estradiol (20 µg/kg, 0.1 ml /d), while the control group was treated with an equivalent amount of sesame oil. Every group was injected with subcutaneous injection for 7 days. The treatment group was randomly divided into three groups to receive the following: TST at 150 mg/kg, ip.; TST at 250 mg/kg, ip.; or sterile normal saline, ip. The groups received these dosages every 2 days for 2 weeks. Lesion growth, histological examination, and protein expression were subsequently analyzed using caliper measurement, histology, immunostaining, and Western blot after each rat received an injection in its own group.

Results: Our results showed that FOXM1 is enriched in nucleus of an ectopic endometrium when compared with a eutopic uterus. Furthermore, we found that an ERK/FOXM1/matrix metalloproteinase-9 (MMP9) signaling pathway might result in the establishment and development of endometriosis. Finally, a thiostrepton concentration dependently reduced the expression of FOXM1, MMP9 and Bcl-2 in endometriotic lesions of the treated rats. Statistical significance was accepted for a value of P < 0.05.

Conclusion: We postulate that thiostrepton could inhibit the endometriotic lesions, at least in part, by decreasing the FOXM1 expression and exerting a pro-apoptotic effect. We reported for the first time that FOXM1 expresses in experimental endometriosis rat and thiostrepton may also be suitable for the administration of endometriosis by inhibiting the growth of endometriotic implants. More studies are needed to further evaluate thiostrepton’s effect.

Keywords: FOXM1, endometriosis, thiostrepton, estrogen, animal model, eutopic uterus.

Mishra, V.V.; Gaddagi, R.A.; Aggarwal, R.; Choudhary, S.; Sharma, U.; Patel, U. Prevalence; characteristics and management of endometriosis amongst infertile women: A one year retrospective study. J. Clin. Diagn. Res., 2015, 9, QC01-QC03.
Menakaya, U.; Infante, F.; Condous, G. Consensus on current management of endometriosis. Hum. Reprod., 2013, 28(11), 3162-3163.
Ozawa, Y.; Murakami, T.; Terada, Y.; Yaegashi, N.; Okamura, K.; Kuriyama, S.; Tsuji, I. Management of the pain associated with endometriosis: An update of the painful problems. Tohoku J. Exp. Med., 2006, 210(3), 175-188.
Ferrero, S.; Remorgida, V.; Maganza, C.; Venturini, P.L.; Salvatore, S.; Papaleo, E.; Candiani, M.; Leone, R.; Maggiore, U. Aromatase and endometriosis: Estrogens play a role. Ann. N. Y. Acad. Sci., 2014, 1317, 17-23.
Taylor, R.N.; Kane, M.A.; Sidell, N. Pathogenesis of endometriosis: Roles of retinoids and inflammatory pathways. Semin. Reprod. Med., 2015, 33, 246-256.
Benagiano, G.; Brosens, I.; Lippi, D. The history of endometriosis. Gynecol. Obstet. Invest., 2014, 78, 1-9.
Burney, R.O.; Giudice, L.C. Pathogenesis and pathophysiology of endometriosis. Fertil. Steril., 2012, 98, 511-519.
Vlahos, N.F.; Economopoulos, K.P.; Fotiou, S. Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer. Best Pract. Res. Clin. Obstet. Gynaecol., 2010, 24(1), 39-50.
Fan, Q.; Cai, Q.; Xu, Y. FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer. Oncotarget, 2015, 6(29), 27688-27699.
Yu, M.; Tang, Z.; Meng, F.; Tai, M.; Zhang, J.; Wang, R.; Liu, C.; Wu, Q. Elevated expression of FoxM1 promotes the tumor cell proliferation in hepatocellular carcinoma. Tumour Biol., 2016, 37(1), 1289-1297.
Nakamura, S.; Hirano, I.; Okinaka, K.; Takemura, T.; Yokota, D.; Ono, T.; Shigeno, K.; Shibata, K.; Fujisawa, S.; Ohnishi, K. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis, 2010, 31(11), 2012-2021.
Huang, C.; Du, J.; Xie, K. FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis. Biochim. Biophys. Acta, 2014, 1845(2), 104-116.
Ma, R.Y.; Tong, T.H.; Leung, W.Y.; Yao, K.M. Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1. Methods Mol. Biol., 2010, 647, 113-123.
Jin, H.; Park, M.H.; Kim, S.M. 3,3′-Diindolylmethane potentiates paclitaxel-induced antitumor effects on gastric cancer cells through the Akt/FOXM1 signaling cascade. Oncol. Rep., 2015, 33(4), 2031-2036.
Xie, Y.; Li, Y.; Kong, Y. OPN induces FoxM1 expression and localization through ERK 1/2, AKT, and p38 signaling pathway in HEC-1A cells. Int. J. Mol. Sci., 2014, 15(12), 23345-23358.
Gartel, A.L. Thiazole antibiotics siomycin and thiostrepton inhibit the transcriptional activity of FOXM1. Front. Oncol., 2013, 3, 150.
Vernon, M.W.; Wilson, E.A. Studies on the surgical induction of endometriosis in the rat. Fertil. Steril., 1985, 44(5), 684-694.
Zhang, H.; Zhao, X.; Liu, S.; Li, J.; Wen, Z.; Li, M. 17betaE2 promotes cell proliferation in endometriosis by decreasing PTEN via NFkappaB-dependent pathway. Mol. Cell. Endocrinol., 2010, 317(1-2), 31-43.
Gori, I.; Pellegrini, C.; Staedler, D.; Russell, R.; Jan, C.; Canny, G.O. Tumor necrosis factor-alpha activates estrogen signaling pathways in endometrial epithelial cells via estrogen receptor alpha. Mol. Cell. Endocrinol., 2011, 345(1-2), 27-37.
Ngô, C.; Nicco, C.; Leconte, M.; Chéreau, C.; Arkwright, S.; Vacher-Lavenu, M.C.; Weill, B.; Chapron, C.; Batteux, F. Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo. J. Pathol., 2010, 222(2), 148-157.
Leconte, M.; Nicco, C.; Ngô, C.; Arkwright, S.; Chéreau, C.; Guibourdenche, J.; Weill, B.; Chapron, C.; Dousset, B.; Batteux, F. Antiproliferative effects of cannabinoid agonists on deep infiltrating endometriosis. Antiproliferative effects of cannabinoid agonists on deep infiltrating endometriosis. Am. J. Pathol., 2010, 177(6), 2963-2970.
Pearce, C.L.; Templeman, C.; Rossing, M.A.; Lee, A.; Near, A.M.; Webb, P.M.; Nagle, C.M.; Doherty, J.A.; Cushing-Haugen, K.L.; Wicklund, K.G.; Chang-Claude, J.; Hein, R.; Lurie, G.; Wilkens, L.R.; Carney, M.E.; Goodman, M.T.; Moysich, K.; Kjaer, S.K.; Hogdall, E.; Jensen, A.; Goode, E.L.; Fridley, B.L.; Larson, M.C.; Schildkraut, J.M.; Palmieri, R.T.; Cramer, D.W.; Terry, K.L.; Vitonis, A.F.; Titus, L.J.; Ziogas, A.; Brewster, W.; Anton-Culver, H.; Gentry-Maharaj, A.; Ramus, S.J.; Anderson, A.R.; Brueggmann, D.; Fasching, P.A.; Gayther, S.A.; Huntsman, D.G.; Menon, U.; Ness, R.B.; Pike, M.C.; Risch, H.; Wu, A.H.; Berchuck, A. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol., 2012, 13(4), 385-394.
Rossing, M.A.; Cushing-Haugen, K.L.; Wicklund, K.G.; Doherty, J.A.; Weiss, N.S. Risk of epithelial ovarian cancer in relation to benign ovarian conditions and ovarian surgery. Cancer Causes Control, 2008, 19(10), 1357-1364.
Xue, J.; Lin, X.; Chiu, W.T.; Chen, Y.H.; Yu, G.; Liu, M.
Feng, X.H.; Sawaya, R.; Medema, R.H.; Hung, M.C.; Huang, S. Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-beta-dependent cancer metastasis. J. Clin. Invest., 2014, 124(2), 564-579.
Cheng, S.L.; Wang, H.C.; Yu, C.J.; Tsao, P.N.; Carmeliet, P.; Cheng, S.J.; Yang, P.C. Prevention of elastase-induced emphysema in placenta growth factor knock-out mice. Respir. Res., 2009, 10, 115.
Jiang, L.; Wu, X.; Wang, P.; Wen, T.; Yu, C.; Wei, L.; Chen, H. Targeting FoxM1 by thiostrepton inhibits growth and induces apoptosis of laryngeal squamous cell carcinoma. J. Cancer Res. Clin. Oncol., 2015, 141, 971-981.
Ahmed, M.; Uddin, S.; Hussain, A.R.; Alyan, A.; Jehan, Z.; Al-Dayel, F.; Al-Nuaim, A.; Al-Sobhi, S.; Amin, T.; Bavi, P.; Al-Kuraya, K.S. FoxM1 and its association with matrix Metalloproteinases (MMP) signaling pathway in papillary thyroid carcinoma. J. Clin. Endocrinol. Metab., 2012, 97(1), E1-E13.
Nicolaou, K.C.; Zak, M.; Rahimipour, S.; Estrada, A.A.; Lee, S.H.; O’Brate, A.; Giannakakou, P.; Ghadiri, M.R. Discovery of a biologically active thiostrepton fragment. J. Am. Chem. Soc., 2005, 127(43), 15042-15044.
Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev., 2001, 15(22), 2922-2933.
Nishida, M.; Nasu, K.; Ueda, T.; Fukuda, J.; Takai, N.; Miyakawa, I. Endometriotic cells are resistant to interferon-gamma-induced cell growth inhibition and apoptosis: A possible mechanism involved in the pathogenesis of endometriosis. Mol. Hum. Reprod., 2005, 11(1), 29-34.
Amaral, J.D.; Solá, S.; Steer, C.J.; Rodrigues, C.M. Role of nuclear steroid receptors in apoptosis. Curr. Med. Chem., 2009, 16(29), 3886-3902.

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Article Details

Year: 2019
Page: [323 - 329]
Pages: 7
DOI: 10.2174/1871520618666180108100211
Price: $65

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