Apoptotic and cytotoxicity effects of All Trans Retinoic Acid (ATRA) in cultured human uterine myoma

Taravat Fakheri, Homa Badri, Ali Mostafaei, Hamidreza Mohammadimotlagh, Mansour Rezaei, Anisodole Nankali



Background: Uterine leiomyoma is the most common tumor among the female in the reproductive period. The first step to control the tumor is employing medical treatment. Currently GnRH agonists are the most common drugs for medical therapy of uterine myoma.  Climacteric-like symptoms and osteoporosis and recurrence of the size of tumor after GnRH agonists consumption are among the most common side effects of employing the medical treatment. In the present study the apoptotic and cytotoxicity effects of All Trans Retinoic Acid (ATRA) on cultured human leiomyoma cells were investigated.

Methods: Samples were myoma cells of women with myomatosis uterine admitted in Imam Reza hospital of Kermanshah. After preparation and counting by neobar lam, they were cultured for 24 hours. Then they were divided into exposed and control groups. The experimental group exposed to ascending concentrations of ATRA and the control group did not have any intervention. After exposure, the cells were cultured for 72 hours. Finally the apoptosis and cytotoxicity were measured using TUNEL method and LDH kit respectively and the results were compared.

Results: The results indicated that apoptotic effects of ATRA were significantly higher than those of control group (P<0.01). Cytotoxicity rate of ATRA was higher than that of control group.

Conclusion: The above findings support the hypothesis that probably retinoic acid pathway is one of the main pathways in myoma pathogenesis. It is possible that this patll way. Would be used to stopping to growth of myoma.

Keywords: Myoma, ATRA, apoptosis, cell culture



Berek JS. Berek and Novak’s Gynecology. 15th ed. Lippincott Williams & Wilkins. 2012.

Marino JL, Eskenazi B, Warner M, Samuels S, Vercellini P, Gavoni N, et al. Uterine leiomyoma and menstrual cycle characteristics in a population-based cohort study. Hum Reprod . 2004;19:2350-5.

Kolankaya A, Arici A. Myomas and assisted reproductive technologies: when and how to act? Obstet Gynecol Clin North Am. 2006;33:145-52.

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):2177-84

Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. 2003;111(8):1037-54.

Hashimoto K, Azuma C, Kamiura S, Kimura T, Nobunaga T, Kanai T, et al. Clonal determination of uterine leiomyomas by analyzing differential inactivation of the X-chromosome-linked phosphoglycerokinase gene. Gynecol Obstet Invest. 1995;40(3):204-8.

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 3:1182-7.

Englund K, Blanck A, Gustavsson I, Lundkvist U, Sjöblom P, Norgren A, et al. Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinol Metab. 1998;83(11):4092-6.

Nisolle M, Gillerot S, Casanas-Roux F, Squifflet J, Berliere M, Donnez J. Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy. Hum Reprod. 1999;14(11):2844-50.

Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007;87(4):725-36.

Tsibris JC, Segars J, Coppola D, Mane S, Wilbanks GD, O'Brien WF, et al. Insights from gene arrays on the development and growth regulation of uterine leiomyomata. Fertil Steril. 2002;78(1):114-21.

Arslan AA, Gold LI, Mittal K, Suen TC, Belitskaya-Levy I, Tang MS, et al. Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review. Hum Reprod. 2005;20(4):852-63.

Wilson AC, Meethal SV, Bowen RL, Atwood CS. Leuprolide acetate: a drug of diverse clinical applications. Expert Opin Investig Drugs. 2007;16(11):1851-63.

Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Ishimaru T, et al. Cell proliferation effect of GnRH agonist on pathological lesions of women with endometriosis, adenomyosis and uterine myoma. Hum Reprod. 2010;25(11):2878-90.

Wang Y, Matsuo H, Kurachi O, Maruo T. Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells. Eur J Endocrinol. 2002;146(3):447-56.

Zaitseva M, Vollenhoven BJ, Rogers PA. Retinoids regulate genes involved in retinoic acid synthesis and transport in human myometrial and fibroid smooth muscle cells. Hum Reprod. 2008;23(5):1076-86.

Boettger-Tong H, Shipley G, Hsu CJ, Stancel GM. Cultured human uterine smooth muscle cells are retinoid responsive. Proc Soc Exp Biol Med. 1997;215(1):59-65.

Gorsky M, Epstein JB. The effect of retinoids on premalignant oral lesions: focus on topical therapy. Cancer. 2002;95:1258-64

Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database Syst Rev. 2004;6:15–16

Lengfelder E, Saussele S, Weisser A, Buchner T, Hehlmann R. Treatment concepts of acute promyelocytic leukemia. Crit Rev Oncol Hematol. 2005;56:261-74

Decensi A, Serrano D, Bonanni B, Cazzaniga M, Guerrieri-Gonzaga A. Breast cancer prevention trials using retinoids. J Mammary Gland Biol Neoplasia. 2003;8:19-30

Shen Q, Brown PH. Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways. J Mammary Gland Biol Neoplasia. 2003;8:45-73

Kang JL, Wang DY, Wang XX, Yu J. Up-regulation of apoptosis by gonadotrophin-releasing hormone agonist in cultures of endometrial cells from women with symptomatic myomas. Hum Reprod. 2010;25(9):2270-5.

Marill J, Idres N, Capron CC, Nguyen E, Chabot GG. Retinoic acid metabolism and mechanism of action: a review. Curr Drug Metab. 2003;4(1):1-10.

Theodosiou M, Laudet V, Schubert M. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell Mol Life Sci. 2010;67(9):1423-45.

Szondy Z, Reichert U, Fésüs L. Retinoic acids regulate apoptosis of T lymphocytes through an interplay between RAR and RXR receptors. Cell Death Differ. 1998;5(1):4-10.

Malik M, Webb J, Catherino WH. Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells. Clin Endocrinol (Oxf). 2008;69(3):462-70.

DOI: http://dx.doi.org/10.22110/jkums.v17i6.980


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