Generic placeholder image

Current Cancer Therapy Reviews

Editor-in-Chief

ISSN (Print): 1573-3947
ISSN (Online): 1875-6301

Systematic Review Article

The Therapeutic Effects of Bromelain against Colorectal Cancer: A Systematic Review

Author(s): Mojgan Forootan, Mehdi Mohammadian Amiri, Mohammad Darvishi, Catherine M.T. Sherwin and Koruosh Ghanadi*

Volume 20, Issue 4, 2024

Published on: 10 October, 2023

Page: [402 - 409] Pages: 8

DOI: 10.2174/0115733947253563230922092456

Price: $65

Abstract

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide.

Objective: Considering the side effects of chemotherapy treatments, we reviewed the anti-cancer effects and mechanisms of bromelain on colon cancer cells in this study.

Methods: The PRISMA guidelines were followed in the design of this systematic review. Various databases, including PubMed, Web of Science, Cochrane Library, and Scopus, were thoroughly searched. Finally, 14 articles were retrieved after considering the study's inclusion and exclusion criteria. The desired data were extracted, entered into an Excel file, and the study results were reviewed.

Results: According to the included studies, bromelain can significantly reduce the survival and death of cloned cancer cells through different mechanisms. These mechanisms include impeding tumor growth and metastasis by reducing mucins production/secretion and increasing/reducing reactive oxygen species (ROS) production. Moreover, bromelain induces apoptosis via reduced expression of Bcl-2, extracellular signal-related kinase (ERK), Akt, activation caspase system (caspase-3, 7, 8, and 9), and extranuclear p53. Ferroptosis was another mechanism of causing cell death. In addition, bromelain activates the autophagy pathway, lysosome formation, and deregulation of other autophagyrelated proteins.

Conclusion: Bromelain effectively inhibits colon cancer cells' growth, proliferation, and metastasis and reduces their survival by different mechanisms. Therefore, after examining clinical studies, it can be used as an effective drug for treating CRC.

[1]
Sung H, Ferlay J, Siegel RL, 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): 209-49.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz Gastroenterol 2019; 14(2): 89-103.
[http://dx.doi.org/10.5114/pg.2018.81072] [PMID: 31616522]
[3]
Lotfollahzadeh S, Recio-Boiles A, Cagir B. Colon Cancer. StatPearls. Treasure Island (FL): StatPearls Publishing LLC 2022.
[4]
Mattiuzzi C, Sanchis-Gomar F, Lippi G. Concise update on colorectal cancer epidemiology. Ann Transl Med 2019; 7(21): 609.
[http://dx.doi.org/10.21037/atm.2019.07.91] [PMID: 32047770]
[5]
Goldsbury DE, Feletto E, Weber MF, et al. Health system costs and days in hospital for colorectal cancer patients in New South Wales, Australia. PLoS One 2021; 16(11): e0260088.
[http://dx.doi.org/10.1371/journal.pone.0260088] [PMID: 34843520]
[6]
Henderson RH, French D, Maughan T, et al. The economic burden of colorectal cancer across Europe: A population-based cost-of-illness study. Lancet Gastroenterol Hepatol 2021; 6(9): 709-22.
[http://dx.doi.org/10.1016/S2468-1253(21)00147-3] [PMID: 34329626]
[7]
Li YJ, Cao MD, Wang X, Lei L, Peng J, Shi J. Thirty-year changes in disability adjusted life years for colorectal cancer in China: A screening perspective analysis. Zhonghua Liu Xing Bing Xue Za Zhi 2022; 43(9): 1381-7.
[PMID: 36117343]
[8]
Abu-Helalah M, Mustafa H, Alshraideh H, et al. Quality of life and psychological wellbeing of colorectal cancer survivors in the KSA. Asian Pac J Cancer Prev 2022; 23(4): 1301-8.
[http://dx.doi.org/10.31557/APJCP.2022.23.4.1301] [PMID: 35485689]
[9]
Rabeneck L, Horton S, Zauber AG, et al. Colorectal cancer. Cancer: Disease Control Priorities. (3rd ed.). Washington, DC: The International Bank for Reconstruction and Development / The World Bank 2015; p. 3.
[http://dx.doi.org/10.1596/978-1-4648-0349-9_ch6]
[10]
Gertsch J. How scientific is the science in ethnopharmacology? Historical perspectives and epistemological problems. J Ethnopharmacol 2009; 122(2): 177-83.
[http://dx.doi.org/10.1016/j.jep.2009.01.010] [PMID: 19185054]
[11]
Sherwin CMT, Heidari-Soureshjani S. Effects and mechanisms of medicinal plants on healing scars: A systematic review. Curr Tradit Med 2022; 8(1): e221121198156.
[http://dx.doi.org/10.2174/2215083807666211122102406]
[12]
Heidari-Soureshjani S, Sherwin CM. Effects of medicinal plants on human hosts and zoonotic helminthic infections: A systematic review. J Nat Prod 2021; 11(4): 472-90.
[13]
Ghahfarrokhi SH, Heidari-Soureshjani S, Talebi-Boroujeni P, Sherwin CMT. Effect and mechanism of curcumin on bone loss and osteoporosis: A systematic review. Curr Tradit Med 2023; 9(6): e241022210320.
[http://dx.doi.org/10.2174/2215083809666221024090809]
[14]
Amini A, Masoumi-Moghaddam S, Ehteda A, Morris DL. Bromelain and N-acetylcysteine inhibit proliferation and survival of gastrointestinal cancer cells in vitro: Significance of combination therapy. J Exp Clin Cancer Res 2014; 33(1): 92.
[PMID: 25425315]
[15]
Amini A, Masoumi-Moghaddam S, Ehteda A, Liauw W, Morris DL. Potentiation of chemotherapeutics by bromelain and N-acetylcysteine: Sequential and combination therapy of gastrointestinal cancer cells. Am J Cancer Res 2016; 6(2): 350-69.
[PMID: 27186409]
[16]
Varilla C, Marcone M, Paiva L, Baptista J. Bromelain, a group of pineapple proteolytic complex enzymes (ananas comosus) and their possible therapeutic and clinical effects. A Summary. Foods 2021; 10(10): 2249.
[http://dx.doi.org/10.3390/foods10102249] [PMID: 34681298]
[17]
Mohamad NE, Abu N, Yeap SK, Alitheen NB. Bromelain enhances the anti-tumor effects of cisplatin on 4T1 breast tumor model In Vivo. Integr Cancer Ther 2019; 18.
[http://dx.doi.org/10.1177/1534735419880258] [PMID: 31752555]
[18]
Park S, Oh J, Kim M, Jin EJ. Bromelain effectively suppresses Kras-mutant colorectal cancer by stimulating ferroptosis. Anim Cells Syst 2018; 22(5): 334-40.
[http://dx.doi.org/10.1080/19768354.2018.1512521] [PMID: 30460115]
[19]
Chang TC, Wei PL, Makondi PT, Chen WT, Huang CY, Chang YJ. Bromelain inhibits the ability of colorectal cancer cells to proliferate via activation of ROS production and autophagy. PLoS One 2019; 14(1): e0210274.
[http://dx.doi.org/10.1371/journal.pone.0210274] [PMID: 30657763]
[20]
Onken JE, Greer PK, Calingaert B, Hale LP. Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol 2008; 126(3): 345-52.
[http://dx.doi.org/10.1016/j.clim.2007.11.002] [PMID: 18160345]
[21]
Amini A, Masoumi-Moghaddam S, Ehteda A, et al. Abstract LB-007: Synergistic inhibition of human gastric and colorectal cancers by Bromelain and N-acetylcysteine: An in vivo study. Cancer Res 2015; 75 (Suppl. s15): LB-007-7.
[http://dx.doi.org/10.1158/1538-7445.AM2015-LB-007]
[22]
Hale LP. Proteolytic activity and immunogenicity of oral bromelain within the gastrointestinal tract of mice. Int Immunopharmacol 2004; 4(2): 255-64.
[http://dx.doi.org/10.1016/j.intimp.2003.12.010] [PMID: 14996417]
[23]
Amini A, Ehteda A, Masoumi Moghaddam S, Akhter J, Pillai K, Morris DL. Cytotoxic effects of bromelain in human gastrointestinal carcinoma cell lines (MKN45, KATO-III, HT29-5F12, and HT29-5M21). OncoTargets Ther 2013; 6: 403-9.
[PMID: 23620673]
[24]
Romano B, Fasolino I, Pagano E, et al. The chemopreventive action of bromelain, from pineapple stem (Ananas comosus L.), on colon carcinogenesis is related to antiproliferative and proapoptotic effects. Mol Nutr Food Res 2014; 58(3): 457-65.
[http://dx.doi.org/10.1002/mnfr.201300345] [PMID: 24123777]
[25]
Amini A, Masoumi-Moghaddam S, Ehteda A, Liauw W, Morris DL. Depletion of mucin in mucin-producing human gastrointestinal carcinoma: Results from in vitro and in vivo studies with bromelain and N-acetylcysteine. Oncotarget 2015; 6(32): 33329-44.
[http://dx.doi.org/10.18632/oncotarget.5259] [PMID: 26436698]
[26]
Gani MBA, Nasiri R, Hamzehalipour Almaki J, et al. In Vitro antiproliferative activity of fresh pineapple juices on ovarian and colon cancer cell lines. Int J Pept Res Ther 2015; 21(3): 353-64.
[http://dx.doi.org/10.1007/s10989-015-9462-z]
[27]
Ataide JA, Cefali LC, Figueiredo MC, et al. In vitro performance of free and encapsulated bromelain. Sci Rep 2021; 11(1): 10195.
[http://dx.doi.org/10.1038/s41598-021-89376-0] [PMID: 33986357]
[28]
Mekkawy AH, Pillai K, Badar S, et al. Addition of bromelain and acetylcysteine to gemcitabine potentiates tumor inhibition in vivo in human colon cancer cell line LS174T. Am J Cancer Res 2021; 11(5): 2252-63.
[PMID: 34094682]
[29]
Montazeri A, Ramezani M, Mohammadgholi A. Investigation the effect of encapsulated bromelain enzyme in magnetic carbon nanotubes on colorectal cancer cells. Jundishapur J Nat Pharm Prod 2021; 16(3): e108796.
[http://dx.doi.org/10.5812/jjnpp.108796]
[30]
Pakbin B, Dibazar SP, Allahyari S, Shariatifar H, Brück WM, Farasat A. ACE2-inhibitory effects of bromelain and ficin in colon cancer cells. Medicina 2023; 59(2): 301.
[http://dx.doi.org/10.3390/medicina59020301] [PMID: 36837502]
[31]
Wen HK, Valle SJ, Morris DL. Bromelain and acetylcysteine (BromAc®): A novel approach to the treatment of mucinous tumours. Am J Cancer Res 2023; 13(4): 1522-32.
[PMID: 37168359]
[32]
PubChem. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 44263865, Carbohydrate moiety of bromelain. 2004. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Carbohydrate-moiety-of-bromelain (cited 2023 July 15).
[33]
Rajan PK, Dunna NR, Venkatabalasubramanian S. A comprehensive overview on the anti-inflammatory, antitumor, and ferroptosis functions of bromelain: An emerging cysteine protease. Expert Opin Biol Ther 2022; 22(5): 615-25.
[http://dx.doi.org/10.1080/14712598.2022.2042250] [PMID: 35176951]
[34]
Amini Chermahini F, Raeisi E, Aazami MH, Mirzaei A, Heidarian E, Lemoigne Y. Does bromelain-cisplatin combination afford in-vitro synergistic anticancer effects on human prostatic carcinoma cell line, PC3? Galen Med J 2020; 9: e1749.
[http://dx.doi.org/10.31661/gmj.v9i0.1749] [PMID: 34466585]
[35]
Alhmoud JF, Woolley JF, Al Moustafa AE, Malki MI. DNA damage/repair management in cancers. Cancers 2020; 12(4): 1050.
[http://dx.doi.org/10.3390/cancers12041050] [PMID: 32340362]
[36]
Chakraborty AJ, Mitra S, Tallei TE, et al. Bromelain a potential bioactive compound: A comprehensive overview from a pharmacological perspective. Life 2021; 11(4): 317.
[http://dx.doi.org/10.3390/life11040317] [PMID: 33917319]
[37]
Ferris RL, Grandis JR. NF-kappaB gene signatures and p53 mutations in head and neck squamous cell carcinoma. Clin Cancer Res 2007; 13(19): 5663-4.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-1544] [PMID: 17908953]
[38]
Kiani M, Zabihi E, Nafarzadeh S, Nouri HR, Bijani A, Seyedmajidi M. Anti-cancer effect of bromelain and its combination with cisplatin on hn5 cell line (squamous cell carcinoma). J Dent 2022; 23(3): 257-65.
[PMID: 36506883]
[39]
Rajabi S, Maresca M, Yumashev AV, Choopani R, Hajimehdipoor H. The most competent plant-derived natural products for targeting apoptosis in cancer therapy. Biomolecules 2021; 11(4): 534.
[http://dx.doi.org/10.3390/biom11040534] [PMID: 33916780]
[40]
Chaudhry GS, Md Akim A, Sung YY, Sifzizul TMT. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Front Pharmacol 2022; 13: 842376.
[http://dx.doi.org/10.3389/fphar.2022.842376] [PMID: 36034846]
[41]
Yang W, Kang Y, Zhao Q, et al. Herbal formula Yangyinjiedu induces lung cancer cell apoptosis via activation of early growth response 1. J Cell Mol Med 2019; 23(9): 6193-202.
[http://dx.doi.org/10.1111/jcmm.14501] [PMID: 31237749]
[42]
Chen C, Gao H, Su X. Autophagy-related signaling pathways are involved in cancer (Review). Exp Ther Med 2021; 22(1): 710.
[http://dx.doi.org/10.3892/etm.2021.10142] [PMID: 34007319]
[43]
Buzun K, Gornowicz A, Lesyk R, Bielawski K, Bielawska A. Autophagy modulators in cancer therapy. Int J Mol Sci 2021; 22(11): 5804.
[http://dx.doi.org/10.3390/ijms22115804] [PMID: 34071600]
[44]
Musial C, Siedlecka-Kroplewska K, Kmiec Z, Gorska-Ponikowska M. Modulation of autophagy in cancer cells by dietary polyphenols. Antioxidants 2021; 10(1): 123.
[http://dx.doi.org/10.3390/antiox10010123] [PMID: 33467015]
[45]
Kufe DW. Mucins in cancer: Function, prognosis and therapy. Nat Rev Cancer 2009; 9(12): 874-85.
[http://dx.doi.org/10.1038/nrc2761] [PMID: 19935676]
[46]
Wi DH, Cha JH, Jung YS. Mucin in cancer: A stealth cloak for cancer cells. BMB Rep 2021; 54(7): 344-55.
[http://dx.doi.org/10.5483/BMBRep.2021.54.7.064] [PMID: 34154702]
[47]
Aggarwal V, Tuli H, Varol A, et al. Role of reactive oxygen species in cancer progression: Molecular mechanisms and recent advancements. Biomolecules 2019; 9(11): 735.
[http://dx.doi.org/10.3390/biom9110735] [PMID: 31766246]
[48]
Qian Q, Chen W, Cao Y, et al. Targeting reactive oxygen species in cancer via chinese herbal medicine. Oxid Med Cell Longev 2019; 2019: 1-23.
[http://dx.doi.org/10.1155/2019/9240426] [PMID: 31583051]
[49]
Vallejo MJ, Salazar L, Grijalva M. Oxidative stress modulation and ROS-mediated toxicity in cancer: A review on In Vitro models for plant-derived compounds. Oxid Med Cell Longev 2017; 2017: 1-9.
[http://dx.doi.org/10.1155/2017/4586068] [PMID: 29204247]
[50]
Dong S, Li X, Jiang W, Chen Z, Zhou W. Current understanding of ferroptosis in the progression and treatment of pancreatic cancer. Cancer Cell Int 2021; 21(1): 480.
[http://dx.doi.org/10.1186/s12935-021-02166-6] [PMID: 34503532]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy