Effects of Lupeol on Estrogen and Androgen Receptor-Positive Breast and Prostate Cancer Cells Lupeol in ER+ and AR+ BC and PC cells

Mahdieh Nezami Majd (1), Arash Alizadeh (2), Elham Zadeh Hashem (3)
(1) DVM Graduated student, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran, Iran, Islamic Republic of,
(2) Division of Pharmacology and Toxicology, Department of Basic Science, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran, Iran, Islamic Republic of,
(3) Division of Pharmacology and Toxicology, Department of Basic Science, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran, Iran, Islamic Republic of

Abstract

Background: Different reports have shown that prostate and breast cancers are the most common cancers worldwide. Lupeol, a dietary triterpene, provides various beneficial effects including anti-cancer properties. The current study aims to investigate the anti-proliferative and antioxidant effects of lupeol, in line with the effects of lupeol on the expression of estrogen and androgen receptors in breast (MCF-7) and prostate (LNCaP) cancer cell lines.


Methods: MCF-7 and LNCaP cells were incubated with increasing concentrations of the lupeol (1, 10, and 100 µM) for 24h. The cytotoxicity of the lupeol was assessed by MTT and Neutral Red assays. Moreover, TAC (total antioxidant capacity), and gene expression of androgen and estrogen receptors were measured by spectrophotometric and qPCR methods, respectively. Overall, 17 beta-estradiol (E2) (9 nM) and dehydroepiandrosterone (DHEA) (5 µM) were selected as positive controls.


Results: The highest concentration of the lupeol induced cytotoxic effects on MCF-7 and LNCaP cells. Various levels of lupeol at specified time intervals increased TAC levels in comparison with the control group. Moreover, the expression levels of estrogen receptors (α and β) and androgen receptors were negatively affected by lupeol.


Conclusion: The findings of our study indicate that lupeol could serve as a promising, and accessible multi-functional anti-tumor agent against hormone-positive breast and prostate cancers.

Full text article

Generated from XML file

References

Şoica C, Voicu M, Ghiulai R, Dehelean C, Racoviceanu R, Trandafirescu C, et al. Natural compounds in sex hormone-dependent cancers: The role of triterpenes as therapeutic agents. Front Endocrinol (Lausanne). 2021;11:612396. doi:10.3389/fendo.2020.612396.

Siddique HR, Saleem M. Beneficial health effects of lupeol triterpene: a review of preclinical studies. Life Sci. 2011;88(7–8):285–293. doi:10.1016/j.lfs.2010.11.020.

Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31–46. doi: 10.1158/2159-8290.CD-21-1059.

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33. doi:10.3322/caac.21708.

Malekinejad F, Kheradmand F, Khadem-Ansari MH, Malekinejad H. Lupeol synergizes with doxorubicin to induce anti-proliferative and apoptotic effects on breast cancer cells. DARU, J Pharm Sci. 2022;30(1):103–115. doi:10.1007/s40199-022-00436-w.

Fatma H, Jameel M, Siddiqui AJ, Kuddus M, Buali NS, Bahrini I, et al. Chemotherapeutic Potential of Lupeol Against Cancer in Pre-Clinical Model: A Systematic Review and Meta-Analysis. Phytomedicine. 2024;155777. doi:10.1016/j.phymed.2024.155777.

Pitchai D, Roy A, Ignatius C. In vitro evaluation of anticancer potentials of lupeol isolated from Elephantopus scaber L. on MCF-7 cell line. J Adv Pharm Technol Res. 2014;5(4):179–184. doi:10.4103/2231-4040.143037.

Prasad S, Nigam N, Kalra N, Shukla Y. Regulation of signaling pathways involved in lupeol induced inhibition of proliferation and induction of apoptosis in human prostate cancer cells. Mol Carcinog. 2008;47(12):916–224. doi:10.1002/mc.20442.

Siddique HR, Mishra SK, Karnes RJ, Saleem M. Lupeol, a novel androgen receptor inhibitor: implications in prostate cancer therapy. Clin Cancer Res. 2011;17(16):5379–5391. doi:10.1158/1078-0432.CCR-11-0916.

Liu K, Zhang X, Xie L, Deng M, Chen H, Song J, et al. Lupeol and its derivatives as anticancer and anti-inflammatory agents: Molecular mechanisms and therapeutic efficacy. Pharmacol Res. 2021;164:105373. doi:10.1016/j.phrs.2020.105373.

Mennini FS, Aurilio MT, Gazzillo S, Nardone C, Sciattella P, Marcellusi A, et al. An analysis of the social and economic costs of breast cancer in Italy. Int J Environ Res Public Health. 2021;18(17). doi:10.3390/ijerph18179005.

Sorensen S V., Goh JW, Pan F, Chen C, Yardley D, Martín M, et al. Incidence-based cost-of-illness model for metastatic breast cancer in the United States. Int J Technol Assess Health Care. 2012;28(1):12–21. doi:10.1017/S026646231100064X.

Welboren W-J, Sweep FCGJ, Span PN, Stunnenberg HG. Genomic actions of estrogen receptor?: what are the targets and how are they regulated? Endocr Relat Cancer. 2009;16(4):1073. doi:10.1677/ERC-09-0086.

Clusan L, Le Goff P, Flouriot G, Pakdel F. A closer look at estrogen receptor mutations in breast cancer and their implications for estrogen and antiestrogen responses. Int J Mol Sci. 2021;22(2):756. doi:10.3390/ijms22020756.

Gruvberger S. Estrogen receptor alpha and beta in breast cancer-gene expression profiles and clinical implications. Department of Oncology, Clinical Sciences, Lund University; 2005. 96 p. doi:10.1016/j.ejso.2004.02.010.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660.

Kim TJ, Lee YH, Koo KC. Current status and future perspectives of androgen receptor inhibition therapy for prostate cancer: a comprehensive review. Biomolecules. 2021;11(4):492. doi:10.3390/biom11040492.

Amini P, Moazamiyanfar R, Dakkali MS, Khani A, Jafarzadeh E, Mouludi K, et al. Resveratrol in cancer therapy: from stimulation of genomic stability to adjuvant cancer therapy: a comprehensive review. Curr Top Med Chem. 2023;23(8):629–648. doi:10.2174/1568026623666221014152759.

Ahmed M, Khan MI, Khan MR, Muhammad N, Khan AU, Khan RA. Role of medicinal plants in oxidative stress and cancer. Sci Rep. 2013;2(1):641–644. doi:10.4172/scientificreports.641.

Amini P, Moazamiyanfar R, Dakkali MS, Jafarzadeh E, Ganjizadeh M, Rastegar-Pouyani N, et al. Induction of cancer cell death by apigenin: a review on different cell death pathways. Mini Rev Med Chem. 2023;23(14):1461–1478. doi:10.2174/1389557523666230119110744.

ECACC. Fundamental Techniques in Cell Culture. SIGMA Lab. 2008;1–61.

Kamiloğlu Beştepe S, Sarı G, Özdal T, Çapanoğlu Güven E. Guidelines for cell viability assays. FOOD Front. 2020;1(3). doi:10.1002/fft2.44.

Varasteh S, Braber S, Kraneveld AD, Garssen J, Fink-Gremmels J. l-Arginine supplementation prevents intestinal epithelial barrier breakdown under heat stress conditions by promoting nitric oxide synthesis. Nutr Res. 2018 Sep;57:45–55. doi:10.1016/j.nutres.2018.05.007.

Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V. Method for the measurement of antioxidant activity in human fluids. J Clin Pathol. 2001;54(5):356–61. doi:10.1136/jcp.54.5.356.

Chomczynski P, Sacchi N. The single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction: twenty-something years on. Nat Protoc. 2006;1(2):581–585. doi:10.1038/nprot.2006.83.

Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Vol. 5, Nature Reviews Disease Primers. 2019. doi:10.1038/s41572-019-0111-2.

Lawhn-Heath C, Salavati A, Behr SC, Rowe SP, Calais J, Fendler WP, et al. Prostate-specific Membrane Antigen PET in Prostate Cancer. Radiology. 2021 May;299(2):248–260. doi:10.1148/radiol.2021202771.

Barbieri CE, Tomlins SA. The prostate cancer genome: Perspectives and potential. Urol Oncol Semin Orig Investig. 2014;32(1):53.e15-53.e22. doi:10.1016/j.urolonc.2013.08.025.

Sloan M, Cancer K, City NY, City NY. Estrogen Receptor-Positive Breast Cancer : Exploiting Signaling Pathways Implicated in Endocrine Resistance. 2018;528–539. doi:10.1634/theoncologist.2017-0423.

Martins WK, Costa ÉT, Cruz MC, Stolf BS, Miotto R, Cordeiro RM, et al. Parallel damage in mitochondrial and lysosomal compartments promotes efficient cell death with autophagy : The case of the pentacyclic triterpenoids. Nat Publ Gr. 2015;(June):1–17. doi:10.1038/srep12425.

Santiago LA, Mayor ABR. L upeol : A n antioxidant triterpene in F icus pseudopalma B lanco. Asian Pac J Trop Biomed. 2014;4(2):109–118. doi:10.1016/S2221-1691(14)60218-5.

Extract L, Crateva OF, Oliv A, Tchimene MK, Nwaehujor CO, Ezenwali M, et al. Free Radical Scavenging Activity of Lupeol Isolated from the Methanol Leaf Extract of Crateva adansonii Oliv . (Capparidaceae). International Journal of Pharmacognosy and Phytochemical Research. 2016; 8(3); 419-426.

Pérez-González MZ, Nieto-Trujillo A, Gutiérrez-Rebolledo GA, García-Martínez I, Estrada-Zúñiga ME, Bernabé-Antonio A, et al. Lupeol acetate production and antioxidant activity of a cell suspension culture from Cnidoscolus chayamansa leaves. South African J Bot. 2019;125:30–38. doi:10.1016/j.sajb.2019.06.030.

Qin A, Qin J, Jin Y, Xie W, Fan L, Jiang L, et al. DHEA improves the antioxidant capacity of endometrial stromal cells and improves endometrium receptivity via androgen receptor. Eur J Obstet Gynecol Reprod Biol. 2016;198:120–126. doi:10.1016/j.ejogrb.2016.01.016 .

Jin LY, Lv ZD, Wang K, Qian L, Song XX, Li XF, et al. Estradiol alleviates intervertebral disc degeneration through modulating the antioxidant enzymes and inhibiting autophagy in the model of menopause rats. Oxid Med Cell Longev. 2018;2018:7890291. doi:.org/10.1155/2018/7890291.

Ding X, Yu L, Ge C, Ma H. Protective effect of DHEA on hydrogen peroxide-induced oxidative damage and apoptosis in primary rat Leydig cells. 2017;8(10):16158–16169. doi:10.18632%2Foncotarget.15300.

Son HJ, Kim N, Song C, Lee SM, Lee H, Surh Y. 17 β -Estradiol reduces inflammation and modulates antioxidant enzymes in colonic epithelial cells. The Korean Journal of Internal Medicine. 2020 Mar;35(2):310. doi:10.3904/kjim.2018.098.

Gorrini C, Gang BP, Bassi C, Wakeham A, Pegah S, Hao Z. Estrogen controls the survival of BRCA1-deficient cells via a PI3K – NRF2-regulated pathway. Proceedings of the National Academy of Sciences. 2014 Mar 25;111(12):4472-4477. doi:10.1073/pnas.1324136111.

Abiramasundari G, Mohan Gowda CM, Sreepriya M. Selective Estrogen Receptor Modulator and prostimulatory effects of phytoestrogen β-ecdysone in Tinospora cordifolia on osteoblast cells. J Ayurveda Integr Med. 2018;9(3):161–168. doi:10.1016/j.jaim.2017.04.003.

Wardell SE, Nelson ER, McDonnell DP. From empirical to mechanism-based discovery of clinically useful Selective Estrogen Receptor Modulators (SERMs). Steroids. 2014;90:30–38. doi:10.1016/j.steroids.2014.07.013.

Thongon N, Boonmuen N, Suksen K, Wichit P, Chairoungdua A, Tuchinda P, et al. Selective Estrogen Receptor Modulator (SERM)-like Activities of Diarylheptanoid, a Phytoestrogen from Curcuma comosa, in Breast Cancer Cells, Pre-osteoblast Cells, and Rat Uterine Tissues. J Agric Food Chem. 2017;65(17):3490–3496. doi:abs/10.1021/acs.jafc.7b00769.

Zingue S, Ntsa DM, Magne Nde CB, Michel T, Ndinteh DT, Clyne C, et al. Lupeol, the major compound of the dichloromethane extract of Millettia macrophylla Benth (Fabaceae), displays estrogenic effects in ovariectomized rats. Phyther Res. 2019;33(4):949–957. doi:10.1002/ptr.6288.

Clark BJ, Prough RA, Klinge CM. Mechanisms of Action of Dehydroepiandrosterone. 1st ed. Vol. 108, Vitamins and Hormones. Elsevier Inc.; 2018. 29–73 p. doi:10.1016/bs.vh.2018.02.003.

Capellino S, Straub RH, Cutolo M. Aromatase and regulation of the estrogen-to-androgen ratio in synovial tissue inflammation : common pathway in both sexes. 2014;1317:24–31. doi:10.1111/nyas.12398.

Khan MA, Singh D, Fatma H, Akhtar K, Arjmand F, Maurya S, et al. Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol. Drug Chem Toxicol. 2022;1–12. doi:10.1080/01480545.2022.2040528

Bhatt M, Patel M, Adnan M, Reddy MN. Anti-metastatic effects of lupeol via the inhibition of MAPK/ERK pathway in lung cancer. Anti-Cancer Agents Med Chem (Formerly Curr Med Chem Agents). 2021;21(2):201–206. doi:10.2174/1871520620666200424131548.

Saleem M, Murtaza I, Tarapore RS, Suh Y, Adhami VM, Johnson JJ, et al. Lupeol inhibits proliferation of human prostate cancer cells by targeting β-catenin signaling. Carcinogenesis. 2009;30(5):808–817. doi:10.1093/carcin/bgp044.

Zhang X, Gao Z, Chen K, Zhuo Q, Chen M, Wang J, et al. Lupeol inhibits the proliferation and migration of MDA-MB-231 breast cancer cells via a novel crosstalk mechanism between autophagy and the EMT. Food Funct. 2022;13(9):4967–4976. doi:10.1039/D2FO00483F.

Authors

Mahdieh Nezami Majd
Arash Alizadeh
dr.arash.alizadeh@gmail.com (Primary Contact)
Elham Zadeh Hashem
1.
Nezami Majd M, Alizadeh A, Zadeh Hashem E. Effects of Lupeol on Estrogen and Androgen Receptor-Positive Breast and Prostate Cancer Cells : Lupeol in ER+ and AR+ BC and PC cells. Arch Breast Cancer [Internet]. 2024 Oct. 25 [cited 2024 Oct. 30];11(4). Available from: https://archbreastcancer.com/index.php/abc/article/view/999

Article Details