Citrus reticulata fruit peel extract ameliorates testesterone-induced benign prostatic hyperplasia-like phenotypes in rats
Abstract views: 315
/ 
PDF downloads: 152
DOI:
https://doi.org/10.62313/ijpbp.2024.208Keywords:
Citrus reticulata, Gleason score, Benign prostatic hyperplasia, Prostate gland, TestosteroneAbstract
Benign prostatic hyperplasia is a major pathophysiologic event that presents a high risk for prostate cancer (the second most frequently diagnosed cancer in men). The prognosis of conventional therapy for BPH remains poor due to treatment failures. Thus, natural remedies such as botanical drugs remain a promising alternative therapy to be explored for the treatment of BPH and prostate cancer. Citrus fruits, specifically fruit peels of Citrus reticulata (CRE) contain bioactive compounds that exhibit anti-inflammatory properties and have been used in crude form in traditional settings to manage benign prostatic hyperplasia and prostate cancer, however, scientific scrutiny of this ethnobotanical claim remains incomplete. This study assessed the protective effect of CRE in testosterone-induced benign prostatic hyperplasia-like phenotypes in rats. Male Wistar rats (n = 30, 150-200 g) were randomly assigned into six groups (n = 5), and treated for 28 days as follows: control group (normal saline, 5 mg/kg s.c.), model group (testosterone,5 mg/kg, i.p.), the finasteride (1 mg/kg, p.o.), and CRE (50, 100, and 200 mg/kg, p.o.) groups received testosterone (5 mg/kg, i.p.) in the morning and their respective treatments (either finasteride or CRE). All rats were given chow and water ad libitum. On the 28th day, the rats were sacrificed following deep anesthesia. Blood and the prostate gland were collected. Full blood count, serum levels of prostate-specific antigen (PSA), testosterone, C-reactive protein (CRP), and histology of the prostate gland were assessed. Compared to the model, treatment with C. reticulata peel extracts markedly reduced prostate weight, attenuated atresia of the prostatic glands, stromal fibrosis, and mast cell infiltration, and increased glandular secretion. Additionally, serum levels of testosterone, CRP, PSA, and white blood count were reduced in the high-dose C. reticulata peel extract-treated group. Fruit peels of C. reticulata exhibited a protective effect against BPH partly by attenuating inflammatory activity. Thus, this finding provides a rationale for further exploration of CRE for novel anti-BPH molecules that could be used to develop therapeutics against prostate cancer.
References
Abdel-Rahman, T., Hussein, A. S., Beshir, S., Hamed, A. R., Ali, E., & El-Tanany, S. S. (2019). Antimicrobial activity of terpenoids extracted from Annona muricata seeds and its endophytic Aspergillus niger strain SH3 either singly or in combination. Open Access Macedonian Journal of Medical Sciences, 7(19), 3127-3131. https://doi.org/10.3889/oamjms.2019.793 DOI: https://doi.org/10.3889/oamjms.2019.793
Akanni, O. O., Owumi, S. E., Olowofela, O. G., Adeyanju, A. A., Abiola, O. J., & Adaramoye, O. A. (2020). Protocatechuic acid ameliorates testosterone‐induced benign prostatic hyperplasia through the regulation of inflammation and oxidative stress in castrated rats. Journal of Biochemical and Molecular Toxicology, 34, e22502. https://doi.org/10.1002/jbt.22502 DOI: https://doi.org/10.1002/jbt.22502
Archer, M., Dogra, N., & Kyprianou, N. (2020). Inflammation as a driver of prostate cancer metastasis and therapeutic resistance. Cancers, 12(10), 2984. https://doi.org/10.3390/cancers12102984 DOI: https://doi.org/10.3390/cancers12102984
Armstrong, B., Barry, M., Frydenberg, M., Gardiner, R. A., Haines, I., & Carter, S. M. (2017). PSA testing for men at average risk of prostate cancer. Public Health Research and Practice, 27(3), e2731721-2731721-e2731721-2731726. http://dx.doi.org/10.17061/phrp2731721 DOI: https://doi.org/10.17061/phrp2731721
Barupal, T., Meena, M., & Sharma, K. (2019). Inhibitory effects of leaf extract of Lawsonia inermis on Curvularia lunata and characterization of novel inhibitory compounds by GC–MS analysis. Biotechnology Reports, 23, e00335. https://doi.org/10.1016/j.btre.2019.e00335 DOI: https://doi.org/10.1016/j.btre.2019.e00335
Battisti, V., Maders, L. D., Bagatini, M. D., Reetz, L. G. B., Chiesa, J., Battisti, I. E., Gonçalves, J. F., Duarte, M. M., Schetinger, M. R., & Morsch, V. M. (2011). Oxidative stress and antioxidant status in prostate cancer patients: relation to Gleason score, treatment and bone metastasis. Biomedicine & Pharmacotherapy, 65(7), 516-524. https://doi.org/10.1016/j.biopha.2011.06.003 DOI: https://doi.org/10.1016/j.biopha.2011.06.003
Boye, A., Asiamah, E. A., Martey, O., & Ayertey, F. (2024). Citrus limon (L.) Osbeck Fruit Peel Extract Attenuates Carbon Tetrachloride-Induced Hepatocarcinogenesis in Sprague-Dawley Rats. BioMed Research International, 2024, 6673550. https://doi.org/10.1155/2024/6673550 DOI: https://doi.org/10.1155/2024/6673550
Cai, H., Zhang, G., Yan, Z., & Shang, X. (2018). The effect of Xialiqi capsule on testosterone-induced benign prostatic hyperplasia in rats. Evidence-Based Complementary and Alternative Medicine, 2018, 5367814. https://doi.org/10.1155/2018/5367814 DOI: https://doi.org/10.1155/2018/5367814
Campbell, K. J., & Leung, H. Y. (2021). Evasion of cell death: A contributory factor in prostate cancer development and treatment resistance. Cancer Letters, 520, 213-221. https://doi.org/10.1016/j.canlet.2021.07.045 DOI: https://doi.org/10.1016/j.canlet.2021.07.045
Clarke, N. W., Ali, A., Ingleby, F., Hoyle, A., Amos, C. L., Attard, G., Brawley, C., Calvert, J., Chowdhury, S., & Cook, A. (2019). Addition of docetaxel to hormonal therapy in low-and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Annals of Oncology, 30(12), 1992-2003. https://doi.org/10.1093/annonc/mdz396 DOI: https://doi.org/10.1093/annonc/mdz396
Corn, P. G., Heath, E. I., Zurita, A., Ramesh, N., Xiao, L., Sei, E., Li-Ning-Tapia, E., Tu, S. M., Subudhi, S. K., & Wang, J. (2019). Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1–2 trial. The Lancet Oncology, 20(10), 1432-1443. https://doi.org/10.1016/S1470-2045(19)30408-5 DOI: https://doi.org/10.1016/S1470-2045(19)30408-5
Dalal, M., Soni, H., Patel, D. J., Mandal, S. D., & Vashi, J. D. (2022). Anti-BPH Activity of Polyherbal Formulation on Testosterone Induced Benign Prostatic Hyperplasia in Rats. Journal of Natural Remedies, 22(4), 617-627. https://doi.org/10.18311/jnr/2022/31346 DOI: https://doi.org/10.18311/jnr/2022/31346
Delahunt, B., Miller, R. J., Srigley, J. R., Evans, A. J., & Samaratunga, H. (2012). Gleason grading: past, present and future. Histopathology, 60, 75-86. https://doi.org/10.1111/j.1365-2559.2011.04003.x DOI: https://doi.org/10.1111/j.1365-2559.2011.04003.x
Doat, S., Cénée, S., Trétarre, B., Rebillard, X., Lamy, P. J., Bringer, J. P., Iborra, F., Murez, T., Sanchez, M., & Menegaux, F. (2017). Nonsteroidal anti‐inflammatory drugs (NSAID s) and prostate cancer risk: results from the EPICAP study. Cancer Medicine, 6(10), 2461-2470. https://doi.org/10.1002/cam4.1186 DOI: https://doi.org/10.1002/cam4.1186
Drudge-Coates, L., Oh, W. K., Tombal, B., Delacruz, A., Tomlinson, B., Ripley, A. V., Mastris, K., O'Sullivan, J. M., & Shore, N. D. (2018). Recognizing symptom burden in advanced prostate cancer: a global patient and caregiver survey. Clinical Genitourinary Cancer, 16(2), e411-e419. https://doi.org/10.1016/j.clgc.2017.09.015 DOI: https://doi.org/10.1016/j.clgc.2017.09.015
Duskova, K., & Vesely, S. (2015). Prostate specific antigen: Current clinical application and future prospects. Biomedical Papers of the Medical Faculty of Palacky University in Olomouc, 159(1), 18-26. http://dx.doi.org/10.5507/bp.2014.046 DOI: https://doi.org/10.5507/bp.2014.046
El Hazzam, K., Hafsa, J., Sobeh, M., Mhada, M., Taourirte, M., El Kacimi, K., & Yasri, A. (2020). An insight into saponins from Quinoa (Chenopodium quinoa Willd): A review. Molecules, 25(5), 1059. https://doi.org/10.3390/molecules25051059 DOI: https://doi.org/10.3390/molecules25051059
Epstein, J. I., Egevad, L., Amin, M. B., Delahunt, B., Srigley, J. R., & Humphrey, P. A. (2016). The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: Definition of grading patterns and proposal for a new grading system. The American Journal of Surgical Pathology, 40(2), 244-252. https://doi.org/10.1097/PAS.0000000000000530 DOI: https://doi.org/10.1097/PAS.0000000000000530
Gerald, T., & Raj, G. (2022). Testosterone and the androgen receptor. Urologic Clinics, 49(4), 603-614. https://doi.org/10.1016/j.ucl.2022.07.004 DOI: https://doi.org/10.1016/j.ucl.2022.07.004
Hatano, K., Fujita, K., & Nonomura, N. (2020). Application of anti-inflammatory agents in prostate cancer. Journal of Clinical Medicine, 9(8), 2680. https://doi.org/10.3390/jcm9082680 DOI: https://doi.org/10.3390/jcm9082680
Hirano, T., Abe, K., Gotoh, M., & Oka, K. (1995). Citrus flavone tangeretin inhibits leukaemic HL-60 cell growth partially through induction of apoptosis with less cytotoxicity on normal lymphocytes. British Journal of Cancer, 72(6), 1380-1388. https://doi.org/10.1038/bjc.1995.518 DOI: https://doi.org/10.1038/bjc.1995.518
Humphrey, P. A. (2017). Histopathology of prostate cancer. Cold Spring Harbor Perspectives in Medicine, 7(10), a030411. https://doi.org/10.1101/cshperspect.a030411 DOI: https://doi.org/10.1101/cshperspect.a030411
Jeong, K. H., Jeon, M. T., Kim, H. D., Jung, U. J., Jang, M. C., Chu, J. W., Yang, S. J., Choi, I. Y., Choi, M. S., & Kim, S. R. (2015). Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease. Journal of Medicinal Food, 18(4), 409-414. https://doi.org/10.1089/jmf.2014.3241 DOI: https://doi.org/10.1089/jmf.2014.3241
Jones, D., Friend, C., Dreher, A., Allgar, V., & Macleod, U. (2018). The diagnostic test accuracy of rectal examination for prostate cancer diagnosis in symptomatic patients: a systematic review. BMC Family Practice, 19, 79. https://doi.org/10.1186/s12875-018-0765-y DOI: https://doi.org/10.1186/s12875-018-0765-y
Kimura, J., Shimizu, K., Kajima, K., Yokosuka, A., Mimaki, Y., Oku, N., & Ohizumi, Y. (2018). Nobiletin reduces intracellular and extracellular β-amyloid in iPS cell-derived Alzheimer’s disease model neurons. Biological and Pharmaceutical Bulletin, 41(4), 451-457. https://doi.org/10.1248/bpb.b17-00364 DOI: https://doi.org/10.1248/bpb.b17-00364
Klimek-Szczykutowicz, M., Szopa, A., & Ekiert, H. (2020). Citrus limon (Lemon) phenomenon—a review of the chemistry, pharmacological properties, applications in the modern pharmaceutical, food, and cosmetics industries, and biotechnological studies. Plants, 9(1), 119. https://doi.org/10.3390/plants9010119 DOI: https://doi.org/10.3390/plants9010119
Kuntal, D., Raman, D., Sivaraman, G., & Ellath, R. P. (2018). Phytochemical screening for various secondary metabolites, antioxidant, and anthelmintic activity of Coscinium fenestratum fruit pulp: a new biosource for novel drug discovery. Turkish Journal of Pharmaceutical Sciences, 15(2), 156-165. https://doi.org/10.4274/tjps.54376 DOI: https://doi.org/10.4274/tjps.54376
Kyprianou, N., Bruckheimer, E., & Guo, Y. (2000). Cell proliferation and apoptosis in prostate cancer: significance in disease progression and therapy. Histology and Histopathology, 15(4), 1211-1223. https://doi.org/10.14670/HH-15.1211
Leslie, S., Soon-Sutton, T., Sajjad, H., & Siref, L. (2023). Prostate Cancer. [Updated 2023 Nov 13]. In StatPearls [Internet]: Treasure Island (FL): StatPearls Publishing.
Li, J., Tian, Y., Guo, S., Gu, H., Yuan, Q., & Xie, X. (2018). Testosterone-induced benign prostatic hyperplasia rat and dog as facile models to assess drugs targeting lower urinary tract symptoms. PloS One, 13(1), e0191469. https://doi.org/10.1371/journal.pone.0191469 DOI: https://doi.org/10.1371/journal.pone.0191469
Libby, P. (2007). Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutrition Reviews, 65(suppl_3), S140-S146. https://doi.org/10.1111/j.1753-4887.2007.tb00352.x DOI: https://doi.org/10.1111/j.1753-4887.2007.tb00352.x
Lv, X., Zhao, S., Ning, Z., Zeng, H., Shu, Y., Tao, O., Xiao, C., Lu, C., & Liu, Y. (2015). Citrus fruits as a treasure trove of active natural metabolites that potentially provide benefits for human health. Chemistry Central Journal, 9, 68. https://doi.org/10.1186/s13065-015-0145-9 DOI: https://doi.org/10.1186/s13065-015-0145-9
Mazzucchelli, R., Colanzi, P., Pomante, R., Muzzonigro, G., & Montironi, R. (2000). Prostate tissue and serum markers. Advances in Clinical Pathology: The Official Journal of Adriatic Society of Pathology, 4(3), 111-120.
Miernik, A., & Gratzke, C. (2020). Current treatment for benign prostatic hyperplasia. Deutsches Ärzteblatt International, 117(49), 843-854. https://doi.org/10.3238/arztebl.2020.0843 DOI: https://doi.org/10.3238/arztebl.2020.0843
Morley, K. L., Ferguson, P. J., & Koropatnick, J. (2007). Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Letters, 251(1), 168-178. https://doi.org/10.1016/j.canlet.2006.11.016 DOI: https://doi.org/10.1016/j.canlet.2006.11.016
Ni Raghallaigh, H., & Eeles, R. (2022). Genetic predisposition to prostate cancer: an update. Familial Cancer, 21, 101-114. https://doi.org/10.1007/s10689-021-00227-3 DOI: https://doi.org/10.1007/s10689-021-00227-3
Njoroge, R. W., Macharia, B. N., Sawe, D. J., & Maiyoh, G. K. (2015). Effects of crude kerosene on testosterone levels, aggression and toxicity in rat. Toxicology Reports, 2, 175-183. https://doi.org/10.1016/j.toxrep.2014.11.017 DOI: https://doi.org/10.1016/j.toxrep.2014.11.017
O’Brian, D., Prunty, M., Hill, A., & Shoag, J. (2021). The role of C-reactive protein in kidney, bladder, and prostate cancers. Frontiers in Immunology, 12, 721989. https://doi.org/10.3389/fimmu.2021.721989 DOI: https://doi.org/10.3389/fimmu.2021.721989
Oh, B., Figtree, G., Costa, D., Eade, T., Hruby, G., Lim, S., Elfiky, A., Martine, N., Rosenthal, D., & Clarke, S. (2016). Oxidative stress in prostate cancer patients: A systematic review of case control studies. Prostate International, 4(3), 71-87. https://doi.org/10.1016/j.prnil.2016.05.002 DOI: https://doi.org/10.1016/j.prnil.2016.05.002
Parsons, J. K., Carter, H. B., Platz, E. A., Wright, E. J., Landis, P., & Metter, E. J. (2005). Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Cancer Epidemiology Biomarkers & Prevention, 14(9), 2257-2260. https://doi.org/10.1158/1055-9965.EPI-04-0715 DOI: https://doi.org/10.1158/1055-9965.EPI-04-0715
Pienta, K. J., Replogle, T., & Lehr, J. E. (1995). Inhibition of prostate cancer growth by vinblastine and tamoxifen. The Prostate, 26(5), 270-274. https://doi.org/10.1002/pros.2990260507 DOI: https://doi.org/10.1002/pros.2990260507
Rashid, M., Ramesh, M., Shamshavali, K., Dang, A., Patel, H., & Undela, K. (2020). Efficacy and safety of non-steroidal anti-androgens in patients with metastatic prostate cancer: meta-analysis of randomized controlled trials. Reviews on Recent Clinical Trials, 15(1), 34-47. https://doi.org/10.2174/1574887114666191105152404 DOI: https://doi.org/10.2174/1574887114666191105152404
Ravery, V., Fizazi, K., Oudard, S., Drouet, L., Eymard, J. C., Culine, S., Gravis, G., Hennequin, C., & Zerbib, M. (2011). The use of estramustine phosphate in the modern management of advanced prostate cancer. BJU International, 108(11), 1782-1786. https://doi.org/10.1111/j.1464-410X.2011.10201.x DOI: https://doi.org/10.1111/j.1464-410X.2011.10201.x
Rawla, P. (2019). Epidemiology of prostate cancer. World Journal of Oncology, 10(2), 63-89. https://doi.org/10.14740/wjon1191 DOI: https://doi.org/10.14740/wjon1191
Sarkar, R. R., Parsons, J. K., Bryant, A. K., Ryan, S. T., Kader, A. K., McKay, R. R., D’Amico, A. V., Nguyen, P. L., Hulley, B. J., & Einck, J. P. (2019). Association of treatment with 5α-reductase inhibitors with time to diagnosis and mortality in prostate cancer. JAMA Internal Medicine, 179(6), 812-819. https://doi.org/10.1001/jamainternmed.2019.0280 DOI: https://doi.org/10.1001/jamainternmed.2019.0280
Shafique, K., Proctor, M., McMillan, D., Qureshi, K., Leung, H., & Morrison, D. (2012). Systemic inflammation and survival of patients with prostate cancer: evidence from the Glasgow Inflammation Outcome Study. Prostate Cancer and Prostatic Diseases, 15, 195-201. https://doi.org/10.1038/pcan.2011.60 DOI: https://doi.org/10.1038/pcan.2011.60
Streicher, J., Meyerson, B. L., Karivedu, V., & Sidana, A. (2019). A review of optimal prostate biopsy: indications and techniques. Therapeutic Advances in Urology, 11. https://doi.org/10.1177/1756287219870074 DOI: https://doi.org/10.1177/1756287219870074
Tanzey, S. S., Mossine, A. V., Sowa, A. R., Torres, J., Brooks, A. F., Sanford, M. S., & Scott, P. J. (2020). A spot test for determination of residual TBA levels in 18 F-radiotracers for human use using Dragendorff reagent. Analytical Methods, 12, 5004-5009. https://doi.org/10.1039/D0AY01565B DOI: https://doi.org/10.1039/D0AY01565B
Tikkinen, K. A., Dahm, P., Lytvyn, L., Heen, A. F., Vernooij, R. W., Siemieniuk, R. A., Wheeler, R., Vaughan, B., Fobuzi, A. C., & Blanker, M. H. (2018). Prostate cancer screening with prostate-specific antigen (PSA) test: a clinical practice guideline. BMJ, 362, k3581. https://doi.org/10.1136/bmj.k3581 DOI: https://doi.org/10.1136/bmj.k3581
Vietri, M. T., D’Elia, G., Caliendo, G., Resse, M., Casamassimi, A., Passariello, L., Albanese, L., Cioffi, M., & Molinari, A. M. (2021). Hereditary prostate cancer: genes related, target therapy and prevention. International Journal of Molecular Sciences, 22(7), 3753. https://doi.org/10.3390/ijms22073753 DOI: https://doi.org/10.3390/ijms22073753
Wade, C. A., Goodwin, J., Preston, D., & Kyprianou, N. (2019). Impact of α-adrenoceptor antagonists on prostate cancer development, progression and prevention. American Journal of Clinical and Experimental Urology, 7(1), 46.
Wang, L., Lu, B., He, M., Wang, Y., Wang, Z., & Du, L. (2022). Prostate cancer incidence and mortality: global status and temporal trends in 89 countries from 2000 to 2019. Frontiers in Public Health, 10, 811044. https://doi.org/10.3389/fpubh.2022.811044 DOI: https://doi.org/10.3389/fpubh.2022.811044
Xu, X., Chen, X., Hu, H., Dailey, A. B., & Taylor, B. D. (2015). Current opinion on the role of testosterone in the development of prostate cancer: a dynamic model. BMC Cancer, 15, 806. https://doi.org/10.1186/s12885-015-1833-5 DOI: https://doi.org/10.1186/s12885-015-1833-5
Yamamoto, Y., Ishii, M., Yoshimura, A., Hayashi, T., Kawamura, N., Nagahara, A., Nakai, Y., Nakayama, M., Kakimoto, K. I., & Nishimura, K. (2023). Efficacy of cabazitaxel in patients with metastatic castration‐resistant prostate cancer: A single‐center study in Japan. International Journal of Urology, 30(1), 20-27. https://doi.org/10.1111/iju.15052 DOI: https://doi.org/10.1111/iju.15052
Zhang, X., Zhou, Y., Cheong, M. S., Khan, H., Ruan, C. C., Fu, M., Xiao, J., & Cheang, W. S. (2022). Citri reticulatae pericarpium extract and flavonoids reduce inflammation in RAW 264.7 macrophages by inactivation of MAPK and NF‐κB pathways. Food Frontiers, 3(4), 785-795. https://doi.org/10.1002/fft2.169 DOI: https://doi.org/10.1002/fft2.169
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Alex Boye, Samuel Essien-Baidoo, Ernest Amponsah Asiamah
This work is licensed under a Creative Commons Attribution 4.0 International License.
The papers published in the International Journal of Plant Based Pharmaceuticals are licenced under Creative Commons Attribution 4.0 International Licence (CC BY).
Accepted 2024-05-12
Published 2024-05-14
