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Comparison of the efficacy of gossypol acetate enantiomers in rats with uterine leiomyoma

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Abstract

Gossypol acetate (GA), as the product of racemic gossypol and acetic acid conjugated by hydrogen bond, is hydrolyzed into gossypol to exert its effect on treating uterine leiomyoma (UL), which has been listed in China. But hypokalemia and mild changes of liver function limit its clinical application. It had been reported that the biological activities of gossypol optical isomers were different. In this study, we aimed to clarify whether there were differences in the efficacy of gossypol enantiomers and whether a single gossypol optical isomer could alleviate adverse reactions in the treatment of UL. The results indicated that (−)-GA and (+)-GA had significant therapeutic effect on rats with UL. Interestingly, (−)-GA could better significantly ameliorate the pathological structure, inhibit the secretion of estrogen, and downregulate the expression of estrogen receptor-alpha (ER-α) and progesterone receptor (PR) than (+)-GA. Additionally, (−)-GA could better evidently decrease the symptoms of abnormally elevated inflammatory factors caused by UL. In contrast, (−)-GA and (+)-GA had certain effects on potassium ion concentration in serum, liver and kidney function, and the effects of (+)-GA on liver function were more obvious than (−)-GA. These findings will be of great significance to the drug development of gossypol optical isomers.

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References

  1. Krempl C, Sporer T, Reichelt M, Ahn SJ, Heidel-Fischer H, Vogel H, Heckel DG, Joußen N (2016) Potential detoxification of gossypol by UDP-glycosyltransferases in the two Heliothine moth species Helicoverpa armigera and Heliothis virescens. Insect Biochem Molec 71:49–57

    Article  CAS  Google Scholar 

  2. Liu SL, Kulp SK, Sugimoto Y, Jiang JH, Chang HL, Dowd MK, Wan P, Lin YC (2002) The (-)-enantiomer of gossypol possesses higher anticancer potency than racemic gossypol in human breast cancer. Anticancer Res 22:33–38

    Google Scholar 

  3. Chen CW, Hu S, Tsui KH, Hwang GS, Chen ST, Tang TK, Cheng HT, Yu JW, Wang HC, Juang HH, Wang PS, Wang SW (2018) Anti-inflammatory effects of gossypol on human lymphocytic jurkat cells via regulation of MAPK signaling and cell cycle. Inflammation 41:2265–2274

    Article  CAS  Google Scholar 

  4. Liu ZC, Yang ZT, Fu YH, Li FY, Liang DJ, Zhou ES, Song XJ, Zhang W, Zhang XC, Cao YG, Zhang NS (2013) Protective effect of gossypol on lipopolysaccharide-induced acute lung injury in mice. Inflamm Res 62:499–506

    Article  CAS  Google Scholar 

  5. Kaushal NA, Kaushal DC (2014) Production and characterization of monoclonal antibodies against substrate specific loop region of Plasmodium falciparum lactate dehydrogenase. Immunol Invest 43:556–571

    Article  CAS  Google Scholar 

  6. Gao YN, Tai WB, Wang N, Li X, Jiang SB, Debnath AK, Du LY, Chen SZ (2019) Identification of novel natural products as effective and broad-spectrum anti-zika virus inhibitors. Viruses 11:1019–1036

    Article  CAS  Google Scholar 

  7. Li L, Li Z, Wang KL, Liu YX, Li YQ, Wang QM (2016) Synthesis and antiviral, insecticidal, and fungicidal activities of gossypol derivatives containing alkylimine, oxime or hydrazine moiety. Bioorgan Med Chem 24:474–483

    Article  CAS  Google Scholar 

  8. Ei-Sharaky AS, Newairy AA, Elguindy NM, Elwafa AA (2010) Spermatotoxicity, biochemical changes and histological alteration induced by gossypol in testicular and hepatic tissues of male rats. Food Chem Toxicol 48:3354–3361

    Article  Google Scholar 

  9. Liu YQ, Ma YL, Li Z, Yang Y, Yu B, Zhang ZY, Wang GY (2020) Investigation of inhibition effect of gossypol-acetic acid on gastric cancer cells based on a network pharmacology approach and experimental validation. Drug Des Dev Ther 14:3615–3623

    Article  CAS  Google Scholar 

  10. Beyazit N, Çakran HS, Cabir A, Akışcan Y, Demetgül C (2020) Synthesis, characterization and antioxidant activity of chitosan Schiff base derivatives bearing (-)-gossypol. Carbohyd Polym 240:116333–116341

    Article  CAS  Google Scholar 

  11. Kovacic P (2003) Mechanism of drug and toxic actions of gossypol: focus on reactive oxygen species and electron transfer. Curr Med Chem 10:2711–2718

    Article  CAS  Google Scholar 

  12. Wang XF, Li XQ, Leng XJ, Shan LL, Zhao JX, Wang YT (2014) Effects of dietary cottonseed meal level on the growth, hematological indices, liver and gonad histology of juvenile common carp (Cyprinus carpio). Aquaculture 428:79–87

    Article  Google Scholar 

  13. Santana AT, Guelfi M, Medeiros HCD, Tavares MA, Bizerra PFV (2015) Mechanisms involved in reproductive damage caused by gossypol in rats and protective effects of vitamin E. Biol Res 48:43–50

    Article  Google Scholar 

  14. EI Sabeh M, Saha SK, Afrin S, Islam MS, Borahay MA (2021) Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities. Mol Cell Biochem 476:3513–3536

    Article  Google Scholar 

  15. Geethamala K, Murthy VS, Vani BR, Rao S (2016) Uterine leiomyomas: an enigma. J Midlife Health 7:22–27

    Google Scholar 

  16. Chegini N, Verala J, Luo X, Xu J, Williams RS (2003) Gene expression profile of leiomyoma and myometrium and the effect of gonadotropin releasing hormone analogue therapy. J Soc Gynecol Invest 10:161–171

    Article  CAS  Google Scholar 

  17. Mallick DJ, Eastman A (2020) AT101 [(-)-Gossypol] selectively inhibits MCL1 and sensitizes carcinoma to BH3 mimetics by inducing and stabilizing NOXA. Cancers 12:2298–2313

    Article  CAS  Google Scholar 

  18. Chen Y, Sten M, Nordenskjöld M, Lambert B, Matlin SA, Zhou RH (1986) The effect of gossypol on the frequency of DNA-strand breaks in human leukocytes in vitro. Mutat Res 164:71–78

    Article  CAS  Google Scholar 

  19. Vela L, Marzo I (2015) Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside. Curr Opin Pharmacol 23:74–81

    Article  CAS  Google Scholar 

  20. Wang GP, Nikolovska-Coleska Z, Yang CY, Wang RX, Tang GZ, Guo J, Shangary S, Qiu S, Gao W, Yang DJ, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang SM (2006) Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem 49:6139–6142

    Article  CAS  Google Scholar 

  21. Opydo-Chanek M, Gonzalo O, Marzo I (2017) Multifaceted anticancer activity of BH3 mimetics: current evidence and future prospects. Biochem Pharmacol 136:12–23

    Article  CAS  Google Scholar 

  22. Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337

    Article  CAS  Google Scholar 

  23. Keshmiri-Neghab H, Goliaei B (2014) Therapeutic potential of gossypol: an overview. Pharm Biol 52:124–128

    Article  CAS  Google Scholar 

  24. Heist RS, Fain J, Chinnasami B, Khan W, Molina JR, Sequist LV, Temel JS, Fidias P, Brainerd V, Leopold L, Lynch TJ (2010) Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol 5:1637–1643

    Article  Google Scholar 

  25. Baggstrom MQ, Qi YW, Koczywas M, Argiris A, Johnson EA, Millward MJ, Murphy SC, Erlichman C, Rudin CM, Govindan R (2011) A phase II study of AT-101 (gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol 6:1757–1760

    Article  Google Scholar 

  26. Stein MN, Goodin S, Gounder M, Gibbon D, Moss R, Portal D, Lindquist D, Zhao Y, Takebe N, Tan A, Aisner J, Lin H, Ready N, Mehnert JM (2019) A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors. Invest New Drug 38:855–865

    Article  Google Scholar 

  27. Swiecicki PL, Bellile E, Sacco AG, Pearson AT, Taylor JG, Jackson TL, Chepeha DB, Spector ME, Shuman A, Malloy K, Moyer J, McKean E, McLean S, Sukari A, Wolf GT, Eisbruch A, Prince M, Bradford C, Carey TE, Wang SM, Nör JE, Worden FP (2016) A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. Invest New Drug 34:481–489

    Article  CAS  Google Scholar 

  28. MacVicar GR, Kuzel TM, Curti BD, Poiesz B, Somer BG, Greco FA, Gressler V, Brill K, Leopold L (2008) An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with hormone refractory prostate cancer (HRPC). J Clin Oncol 26:16043–16043

    Article  Google Scholar 

  29. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B (2009) An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 15:3172–3176

    Article  CAS  Google Scholar 

  30. Sonpavde G, Matveev V, Burke JM, Caton JR, Fleming MT, Hutson TE, Galsky MD, Berry WR, Karlov P, Holmlund JT, Wood BA, Brookes M, Leopold L (2012) Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann Oncol 23:1803–1808

    Article  CAS  Google Scholar 

  31. Masuelli L, Benvenuto M, Izzi V, Zago E, Mattera R, Cerbelli B, Potenza V, Fazi S, Ciuffa S, Tresoldi I, Lucarelli E, Modesti A, Bei R (2020) In vivo and in vitro inhibition of osteosarcoma growth by the pan Bcl-2 inhibitor AT-101. Invest New Drug 38:675–689

    Article  CAS  Google Scholar 

  32. Mehner M, Kubelt C, Adamski V, Schmitt C, Synowitz M, Held-Feindt J (2020) Combined treatment of AT101 and demethoxycurcumin yields an enhanced anti-proliferative effect in human primary glioblastoma cells. J Cancer Res Clin Oncol 146:117–126

    Article  CAS  Google Scholar 

  33. Yao J, Li HF, He XW, Li L, Lu Y (2014) Determination of gossypol isomer in compound acetic acid gossypol tablets by HPLC. Chin J Pharm Anal 34:1732–1736

    CAS  Google Scholar 

  34. Zhou MY, Gulisitan A, Li Y, Yao J (2020) Preparation and content determination of gossypol acetate optical isomer. J Xinjiang Med Univ 43:21–24

    CAS  Google Scholar 

  35. Luo N, Guan QY, Zheng LH, Qu XY, Dai H, Cheng ZP (2014) Estrogen-mediated activation of fibroblasts and its effects on the fibroid cell proliferation. Transl Res 163:232–241

    Article  CAS  Google Scholar 

  36. Stewart EA (2001) Uterine fibroids. Lancet 357:293–298

    Article  CAS  Google Scholar 

  37. Shan M, Carlson KE, Bujotzek A, Wellner A, Gust R, Weber M, Katzenellenbogen JA, Haag R (2013) Nonsteroidal bivalent estrogen ligands: an application of the bivalent concept to the estrogen receptor. ACS Chem Biol 8:707–715

    Article  CAS  Google Scholar 

  38. Benassayag C, Leroy MJ, Rigourd V, Robert B, Honoré JC, Mignot TM, Vacher-Lavenu MC, Chapron C, Ferré F (1999) Estrogen receptors (ERalpha/ERbeta) in normal and pathological growth of the human myometrium: pregnancy and leiomyoma. Am J Physiol 276:1112–1118

    Google Scholar 

  39. Couse JF, Lindzey J, Grandien K, Gustafsson JÅ, Korach KS (1997) Tissue distribution and quantitative analysis of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ) messenger ribonucleic acid in the wild-type and ERα-knockout mouse. Endocrinology 138:4613–4621

    Article  CAS  Google Scholar 

  40. Kim JJ, Kurita T, Bulun SE (2013) Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev 34:130–162

    Article  CAS  Google Scholar 

  41. Bodner K, Bodner-adler B, Kimberger O, Czerwenka K, Mayerhofer K (2004) Estrogen and progesterone receptor expression in patients with uterine smooth muscle tumors. Fertil Steril 81:1062–1066

    Article  CAS  Google Scholar 

  42. Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V (2008) Estrogen receptor α and β in uterine fibroids: a basis for altered estrogen responsiveness. Fertil Steril 90:1878–1885

    Article  CAS  Google Scholar 

  43. Kim EH, Kim JY, Lee YH, Chong GO, Park JY, Hong DG (2014) Comparison of estrogen receptor-α, progesterone receptor and calponin expression in gonadotrophin-releasing hormone agonist-sensitive and-resistant uterine fibroids. Obstet Gynecol Sci 57:144–150

    Article  Google Scholar 

  44. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20

    Article  CAS  Google Scholar 

  45. Akira S, Hirano T, Taga T, Kishimoto T (1990) Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J 4:2860–2867

    Article  CAS  Google Scholar 

  46. Gagat M, Zielińska W, Mikołajczyk K, Zabrzyński J, Krajewski A, Klimaszewska-Wiśniewska A, Grzanka D, Grzanka A (2021) CRISPR-based activation of endogenous expression of TPM1 inhibits inflammatory response of primary human coronary artery endothelial and smooth muscle cells induced by recombinant human tumor necrosis factor α. Front Cell Dev Biol 9:668032–668055

    Article  Google Scholar 

  47. Borthakur A, Prabhu YD, Gopalakrishnan AV (2020) Role of IL-6 signalling in polycystic ovarian syndrome associated inflammation. J Reprod Immunol 141:103155–103162

    Article  CAS  Google Scholar 

  48. Liu LX, Li QQ, Yang YJ, Guo AW (2021) Biological function of short-chain fatty acids and its regulation on intestinal health of poultry. Front Vet Sci 8:736739–736751

    Article  Google Scholar 

  49. Peng H, Harvey BT, Richards CI, Nixon K (2021) Neuron-derived extracellular vesicles modulate microglia activation and function. Biology 10:948–960

    Article  CAS  Google Scholar 

  50. Sang GW, Lorenzo B, Reidenberg MM (1991) Inhibitory effects of gossypol on corticosteroid 11-beta-hydroxysteroid dehydrogenase from guinea pig kidney: a possible mechanism for causing hypokalemia. J Steroid biochem molec biol 39:169–176

    Article  CAS  Google Scholar 

  51. Li XX, Du FY, Liu HX, Ji JB, Xing J (2015) Investigation of the active components in Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity. J Ethnopharmacol 162:238–243

    Article  CAS  Google Scholar 

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Acknowledgements

This work was financially supported by Scientific Research Program of the Higher Education Institution of Xinjiang (XJEDU2018I012).

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  1. Jie Yuan and Mengyu Zhou have contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Xinjiang Second Medical College, Karamay, 834000, China

    Jie Yuan & Xiaobing Xin

  2. The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832008, China

    Mengyu Zhou

  3. School of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China

    Jun Yao & Junmin Chang

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  1. Jie Yuan
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Yuan, J., Zhou, M., Xin, X. et al. Comparison of the efficacy of gossypol acetate enantiomers in rats with uterine leiomyoma. J Nat Med 77, 41–52 (2023). https://doi.org/10.1007/s11418-022-01644-z

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