Cinnamophilin ameliorates testosterone-induced prostatic hyperplasia and fibrosis by regulating 5α-reductase and TGF-β/Smad signaling pathway

Document Type : Original Article

Authors

1 College of Basic Medical Sciences, Yichun University, Yichun, Jiangxi Province 336000, China

2 College of Chemistry and Bio-engineering, Yichun University, Yichun, Jiangxi Province 336000, China

3 School of Medical and Health Sciences, Fooyin University, Daliao, Kaohsiung 83102, Taiwan

4 School of Clinical Medicine, Yichun University, Yichun, Jiangxi Province 336000, China

10.22038/ijbms.2025.88921.19197

Abstract

Objective(s): Androgen and TGF-β1/Smad signaling pathways play important roles in epithelial-mesenchymal transition (EMT), fibrosis, and the development of benign prostatic hyperplasia (BPH). Cinnamophilin is extracted from Cinnamomum philippinense. The anti-proliferative and anti-fibrosis effects of cinnamophilin on the prostate remain unclear. This study aimed to investigate the therapeutic effects and molecular mechanism of action of cinnamophilin on prostate growth in testosterone propionate (TP)-treated mice.
Materials and Methods: The study was conducted both in vivo and in vitro. TP was injected subcutaneously to induce prostate enlargement and growth. Cinnamophilin (40 mg/kg) was orally administered once a day in TP (7.5 mg/ kg)-treated mice for 28 days. The morphological characteristics and fibrosis of the prostate were examined by H&E (Hematoxylin and Eosin) and Masson’s trichrome stain. Protein expression was determined by Western blot. BPH-1 and WPMY-1 cells were treated with different concentrations of cinnamophilin (1–100 μM). 
Results: Cinnamophilin (40 mg/kg) significantly reduced prostate weight and prostate index in animal models. Cinnamophilin inhibited the protein expression of 5α-reductase type II and prostate-specific antigen (PSA) in TP-treated mice. Cinnamophilin reversed morphological changes, EMT, and fibrosis in TP-treated mice. Cinnamophilin increased E-cadherin but decreased N-cadherin, vimentin, fibronectin, α-SMA, TGFBR2, TGF-β1, p-Smad2/3, collagen I, collagen III, and collagen IV protein expressions. The expression of Smad2/3 was not significantly different among these groups. Cinnamophilin (100 μM) inhibited proliferation at 48 hr in BPH-1 and WPMY-1 cells. 
Conclusion: These findings suggest that cinnamophilin inhibits prostate growth and mitigates EMT and fibrosis by regulating TGFβ/Smad signaling pathways. 

Keywords

Main Subjects

References

1. Langan RC. Benign prostatic hyperplasia. Prim Care 2019; 46:223-232.
2. Chughtai B, Forde JC, Thomas DD, Laor L, Hossack T, Woo HH, et al. Benign prostatic hyperplasia. Nat Rev Dis Primers 2016; 2:16031.
3. Liu D, Li C, Li Y, Zhou L, Li J, Wang Y, et al. Benign prostatic hyperplasia burden comparison between China and United States based on the global burden of disease study 2019. World J Urol 2023; 41:3629-3634.
4. Collaborators GBDBPH. The global, regional, and national burden of benign prostatic hyperplasia in 204 countries and territories from 2000 to 2019: A systematic analysis for the global burden of disease study 2019. Lancet Healthy Longev 2022; 3:e754-e776.
5. Lucia MS, Lambert JR. Growth factors in benign prostatic hyperplasia: Basic science implications. Curr Urol Rep 2008; 9:272-278.
6. Udensi UK, Tchounwou PB. Oxidative stress in prostate hyperplasia and carcinogenesis. J Exp Clin Cancer Res 2016; 35:139-157.
7. Kwon Y. Use of saw palmetto (Serenoa repens) extract for benign prostatic hyperplasia. Food Sci Biotechnol 2019; 28:1599-1606.
8. Goncharov AP, Vashakidze N, Kharaishvili G. Epithelial-mesenchymal transition: A fundamental cellular and microenvironmental process in benign and malignant prostate pathologies. Biomedicines 2024; 12:418-438.
9. Lu T, Lin WJ, Izumi K, Wang X, Xu D, Fang LY, et al. Targeting androgen receptor to suppress macrophage-induced EMT and benign prostatic hyperplasia (BPH) development. Mol Endocrinol 2012; 26:1707-1715.
10. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442-454.
11. Xu C, Xu Y, Shen Z, Zhou H, Xiao J, Huang T. Effects of metformin on prostatic tissue of rats with metabolic syndrome and benign prostatic hyperplasia. Int Urol Nephrol 2018; 50:611-617.
12. Lin D, Luo C, Wei P, Zhang A, Zhang M, Wu X, et al. YAP1 Recognizes inflammatory and mechanical cues to exacerbate benign prostatic hyperplasia via promoting cell survival and fibrosis. Adv Sci (Weinh) 2024; 11:e2304274.
13. Rao PV, Gan SH. Cinnamon: a multifaceted medicinal plant. Evid Based Complement Alternat Med 2014; 2014:642942.
14. Lee EJ, Chen HY, Lee MY, Chen TY, Hsu YS, Hu YL, et al. Cinnamophilin reduces oxidative damage and protects against transient focal cerebral ischemia in mice. Free Radic Biol Med 2005; 39:495-510.
15. Yu SM, Ko FN, Wu TS, Lee JY, Teng CM. Cinnamophilin, a novel thromboxane A2 receptor antagonist, isolated from Cinnamomum philippinense. Eur J Pharmacol 1994; 256:85-91.
16. Hsiao G, Teng CM, Sheu JR, Cheng YW, Lam KK, Lee YM, et al. Cinnamophilin as a novel antiperoxidative cytoprotectant and free radical scavenger. Biochim Biophys Acta 2001; 1525:77-88.
17. Tai SH, Lin YW, Huang TY, Chang CC, Chao LC, Wu TS, et al. Cinnamophilin enhances temozolomide-induced cytotoxicity against malignant glioma: The roles of ROS and cell cycle arrest. Transl Cancer Res 2021; 10:3906-3920.
18. Jin BR, Kim HJ, Na JH, Lee WK, An HJ. Targeting benign prostate hyperplasia treatments: AR/TGF-beta/NOX4 inhibition by apocynin suppresses inflammation and proliferation. J Adv Res 2024; 57:135-147.
19. Hsui Y, Chen H, Chen C, Chen C. Chemical constituents from the stems of Machilus philippinensis. Chem Nat Compd 2013; 49:79-80.
20. Li Y, Tu B, Wang Z, Shao Z, Fu C, Hua J, et al. Doxazosin attenuates development of testosterone propionate-induced prostate growth by regulating TGF-beta/Smad signaling pathway, prostate-specific antigen expression and reversing epithelial-mesenchymal transition in mice and stroma cells. Curr Mol Pharmacol 2024; 17:e18761429315125.
21. Chen TY, Tai SH, Lee EJ, Huang CC, Lee AC, Huang SY, et al. Cinnamophilin offers prolonged neuroprotection against gray and white matter damage and improves functional and electrophysiological outcomes after transient focal cerebral ischemia. Crit Care Med 2011; 39:1130-1137.
22. Chihomvu P, Ganesan A, Gibbons S, Woollard K, Hayes MA. Phytochemicals in drug discovery-a confluence of tradition and innovation. Int J Mol Sci 2024; 25:8792-8814.
23. Angwa LM, Jiang Y, Pei J, Sun D. Anti-oxidant phytochemicals for the prevention of fluoride-induced oxidative stress and apoptosis: A review. Biol Trace Elem Res 2022; 200:1418-1441.
24. Liu J, Shimizu K, Kondo R. Anti-androgenic activity of fatty acids. Chem Biodivers 2009; 6:503-512.
25. Liao S, Hiipakka RA. Selective inhibition of steroid 5 alpha-reductase isozymes by tea epicatechin-3-gallate and epigallocatechin-3-gallate. Biochem Biophys Res Commun 1995; 214:833-838.
26. Insumrong K, Ingkaninan K, Waranuch N, Tanuphol N, Wisuitiprot W, Promgool T, et al. Isolation and HPLC Quantitative Determination of 5alpha-Reductase Inhibitors from Tectona grandis L.f. leaf extract. Molecules 2022; 27:2893-2904.
27. But MG, Tero-Vescan A, Puscas A, Jitca G, Marc G. Exploring the inhibitory potential of phytosterols beta-sitosterol, stigmasterol, and campesterol on 5-alpha reductase activity in the human prostate: An in vitro and in silico approach. Plants (Basel) 2024; 13:3146-3161.
28. Afify H, Abo-Youssef AM, Abdel-Rahman HM, Allam S, Azouz AA. The modulatory effects of cinnamaldehyde on uric acid level and IL-6/JAK1/STAT3 signaling as a promising therapeutic strategy against benign prostatic hyperplasia. Toxicol Appl Pharmacol 2020; 402:115122.
29. Gopalakrishnan S, Dhaware M, Sudharma AA, Mullapudi SV, Siginam SR, Gogulothu R, et al. Chemopreventive effect of cinnamon and its bioactive compounds in a rat model of premalignant prostate carcinogenesis. Cancer Prev Res (Phila) 2023; 16:139-151.
30. He H, Wang H, Chen X, Zhong Y, Huang XR, Ma RC, et al. Treatment for type 2 diabetes and diabetic nephropathy by targeting Smad3 signaling. Int J Biol Sci 2024; 20:200-217.
31. Al-Trad B, Aljabali A, Al Zoubi M, Shehab M, Omari S. Effect of gold nanoparticles treatment on the testosterone-induced benign prostatic hyperplasia in rats. Int J Nanomedicine 2019; 14:3145-3154.
32. Inui N, Sakai S, Kitagawa M. Molecular pathogenesis of pulmonary fibrosis, with focus on pathways related to TGF-beta and the ubiquitin-proteasome pathway. Int J Mol Sci 2021; 22;6107-6124.
33. Yao Y, Chen R, Wang G, Zhang Y, Liu F. Exosomes derived from mesenchymal stem cells reverse EMT via TGF-beta1/Smad pathway and promote repair of damaged endometrium. Stem Cell Res Ther 2019; 10:225-241.
34. Qiu D, Song S, Chen N, Bian Y, Yuan C, Zhang W, et al. NQO1 alleviates renal fibrosis by inhibiting the TLR4/NF-kappaB and TGF-beta/Smad signaling pathways in diabetic nephropathy. Cell Signal 2023; 108:110712.
35. Marconi GD, Fonticoli L, Rajan TS, Pierdomenico SD, Trubiani O, Pizzicannella J, et al. Epithelial-mesenchymal transition (EMT): The type-2 EMT in wound healing, tissue regeneration and organ fibrosis. Cells 2021; 10:1587-1600.
36. Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 2022; 15:129-155.
37. Royuela M, De Miguel MP, Bethencourt FR, Sanchez-Chapado M, Fraile B, Paniagua R. Transforming growth factor beta 1 and its receptor types I and II. Comparison in human normal prostate, benign prostatic hyperplasia, and prostatic carcinoma. Growth Factors 1998; 16:101-110.
38. Wang Z, Zhang Y, Zhao C, Li Y, Hu X, Wu L, et al. The miR-223-3p/MAP1B axis aggravates TGF-beta-induced proliferation and migration of BPH-1 cells. Cell Signal 2021; 84:110004.
39. Hagenlocher Y, Satzinger S, Civelek M, Feilhauer K, Koninger J, Bischoff SC, et al. Cinnamon reduces inflammatory response in intestinal fibroblasts in vitro and in colitis in vivo leading to decreased fibrosis. Mol Nutr Food Res 2017; 61: doi: 10.1002/mnfr.201601085.
40. Mitamura Y, Murai M, Mitoma C, Furue M. NRF2 activation inhibits both TGF-beta1- and IL-13-mediated periostin expression in fibroblasts: Benefit of cinnamaldehyde for antifibrotic treatment. Oxid Med Cell Longev 2018; 2018:2475047.
Iranian Journal of Basic Medical Sciences
Volume 29, Issue 1
January 2026
Pages 121-127

Files

Share

How to cite

Statistics