Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Caffeic Acid Phenethyl Ester: A Potential Therapeutic Cancer Agent?

In Press, (this is not the final "Version of Record"). Available online 06 November, 2023
Author(s): Geir Bjørklund*, Olha Storchylo, Massimiliano Peana, Tony Hangan*, Roman Lysiuk, Larysa Lenchyk, Oleh Koshovyi, Halyna Antonyak, Nataliia Hudz and Salvatore Chirumbolo
Published on: 06 November, 2023

DOI: 10.2174/0109298673252993230921073502

Price: $95

Abstract

Background: Propolis and its major phenolic compound, caffeic acid phenethyl ester (CAPE), have garnered considerable scientific interest due to their anti-inflammatory properties and potential therapeutic applications.

Objectives: This narrative review explores the potential utility of CAPE in cancer treatment.

Methods: We comprehensively reviewed relevant studies from scientific databases (PubMed and Web of Science) from 2000 to 2022. Our search focused on keywords such as cancer, natural drugs, caffeic acid phenethyl ester, CAPE, cancer cell lines, antitumor effects, and propolis.

Results: CAPE exhibits diverse biological benefits, including antimicrobial, antioxidant, antiviral, anti-inflammatory, cytotoxic, and potentially anti-carcinogenic properties. Numerous studies have demonstrated its wide-ranging antitumor effects on various cancer cell lines, including growth inhibition, apoptosis induction, tumor invasiveness prevention, malignancy suppression, and anti-angiogenic activity.

Conclusion: Following comprehensive preclinical toxicity assessments, further evaluation of CAPE's efficacy and safety through clinical trials is highly recommended to elucidate its potential health benefits in diverse forms of human cancer.

[1]
Durazzo, A.; Lucarini, M.; Souto, E.B.; Cicala, C.; Caiazzo, E.; Izzo, A.A.; Novellino, E.; Santini, A. Polyphenols: A concise overview on the chemistry, occurrence, and human health. Phytother. Res., 2019, 33(9), 2221-2243.
[http://dx.doi.org/10.1002/ptr.6419] [PMID: 31359516]
[2]
Majidinia, M.; Bishayee, A.; Yousefi, B. Polyphenols: Major regulators of key components of DNA damage response in cancer. DNA Repair (Amst.), 2019, 82, 102679.
[http://dx.doi.org/10.1016/j.dnarep.2019.102679] [PMID: 31450085]
[3]
Bułdak, R.J.; Hejmo, T.; Osowski, M.; Bułdak, Ł.; Kukla, M.; Polaniak, R.; Birkner, E. The impact of coffee and its selected bioactive compounds on the development and progression of colorectal cancer in vivo and in vitro. Molecules, 2018, 23(12), 3309.
[http://dx.doi.org/10.3390/molecules23123309] [PMID: 30551667]
[4]
Espíndola, K.M.M.; Ferreira, R.G.; Narvaez, L.E.M.; Silva Rosario, A.C.R.; da Silva, A.H.M.; Silva, A.G.B.; Vieira, A.P.O.; Monteiro, M.C. Chemical and pharmacological aspects of caffeic acid and its activity in hepatocarcinoma. Front. Oncol., 2019, 9, 541.
[http://dx.doi.org/10.3389/fonc.2019.00541] [PMID: 31293975]
[5]
Kabała-Dzik, A.; Rzepecka-Stojko, A.; Kubina, R.; Jastrzębska-Stojko, Ż.; Stojko, R.; Wojtyczka, R.; Stojko, J. Comparison of two components of propolis: Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) induce apoptosis and cell cycle arrest of breast cancer cells MDA-MB-231. Molecules, 2017, 22(9), 1554.
[http://dx.doi.org/10.3390/molecules22091554] [PMID: 28926932]
[6]
Kuo, C.C.; Wang, R.H.; Wang, H.H.; Li, C.H. Meta-analysis of randomized controlled trials of the efficacy of propolis mouthwash in cancer therapy-induced oral mucositis. Support. Care Cancer, 2018, 26(12), 4001-4009.
[http://dx.doi.org/10.1007/s00520-018-4344-5] [PMID: 30022350]
[7]
Waheed, M.; Hussain, M.B.; Javed, A.; Mushtaq, Z.; Hassan, S.; Shariati, M.A.; Khan, M.U.; Majeed, M.; Nigam, M.; Mishra, A.P.; Heydari, M. Honey and cancer: A mechanistic review. Clin. Nutr., 2019, 38(6), 2499-2503.
[http://dx.doi.org/10.1016/j.clnu.2018.12.019] [PMID: 30639116]
[8]
Zabaiou, N.; Fouache, A.; Trousson, A.; Baron, S.; Zellagui, A.; Lahouel, M.; Lobaccaro, J.A. Biological properties of propolis extracts: Something new from an ancient product. Chem Phys Lipids., 2017, 207(Pt B), 214-222.
[http://dx.doi.org/10.1016/j.chemphyslip.2017.04.005]
[9]
Alam, M.; Ahmed, S.; Elasbali, A.M.; Adnan, M.; Alam, S.; Hassan, M.I.; Pasupuleti, V.R. Therapeutic implications of caffeic acid in cancer and neurological diseases. Front. Oncol., 2022, 12, 860508.
[http://dx.doi.org/10.3389/fonc.2022.860508] [PMID: 35359383]
[10]
Mirzaei, S.; Gholami, M.H.; Zabolian, A.; Saleki, H.; Farahani, M.V.; Hamzehlou, S.; Far, F.B.; Sharifzadeh, S.O.; Samarghandian, S.; Khan, H.; Aref, A.R.; Ashrafizadeh, M.; Zarrabi, A.; Sethi, G. Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer. Pharmacol. Res., 2021, 171, 105759.
[http://dx.doi.org/10.1016/j.phrs.2021.105759] [PMID: 34245864]
[11]
Stohs, S.J. Safety and efficacy of shilajit (mumie, moomiyo). Phytother. Res., 2014, 28(4), 475-479.
[http://dx.doi.org/10.1002/ptr.5018] [PMID: 23733436]
[12]
Boisard, S.; Shahali, Y.; Aumond, M.C.; Derbré, S.; Blanchard, P.; Dadar, M.; Le Ray, A.M.; Richomme, P. Anti-AGE activity of poplar-type propolis: Mechanism of action of main phenolic compounds. Int. J. Food Sci. Technol., 2019.
[http://dx.doi.org/10.1111/ijfs.14284]
[13]
Mainasara, M.M.; Abu Bakar, M.F.; C Linatoc, A.A. Malaysian medicinal plants’ potential for breast cancer therapy. Asian J. Pharm. Clin. Res., 2018, 11(6), 101-117.
[http://dx.doi.org/10.22159/ajpcr.2018.v11i6.24322]
[14]
Bjørklund, G.; Dadar, M.; Chirumbolo, S.; Lysiuk, R. Flavonoids as detoxifying and pro-survival agents: What’s new? Food Chem. Toxicol., 2017, 110, 240-250.
[http://dx.doi.org/10.1016/j.fct.2017.10.039] [PMID: 29079495]
[15]
Chirumbolo, S.; Bjørklund, G.; Lysiuk, R.; Vella, A.; Lenchyk, L.; Upyr, T. Targeting cancer with phytochemicals via their fine tuning of the cell survival signaling pathways. Int. J. Mol. Sci., 2018, 19(11), 3568.
[http://dx.doi.org/10.3390/ijms19113568] [PMID: 30424557]
[16]
Lysiuk, R.; Hudz, N. Differential spectrophotometry: Application for quantification of flavonoids in herbal drugs and nutraceuticals. Int. J Trends. Food Nutr. (Roma), 2017, 1, e102.
[17]
Tolba, M.F.; Azab, S.S.; Khalifa, A.E.; Abdel-Rahman, S.Z.; Abdel-Naim, A.B. Caffeic acid phenethyl ester, a promising component of propolis with a plethora of biological activities: A review on its anti-inflammatory, neuroprotective, hepatoprotective, and cardioprotective effects. IUBMB Life, 2013, 65(8), 699-709.
[http://dx.doi.org/10.1002/iub.1189] [PMID: 23847089]
[18]
Akyol, S.; Ozturk, G.; Ginis, Z.; Armutcu, F.; Yigitoglu, M.R.; Akyol, O. In vivo and in vitro antıneoplastic actions of caffeic acid phenethyl ester (CAPE): Therapeutic perspectives. Nutr. Cancer, 2013, 65(4), 515-526.
[http://dx.doi.org/10.1080/01635581.2013.776693] [PMID: 23659443]
[19]
Murtaza, G.; Karim, S.; Akram, M.R.; Khan, S.A.; Azhar, S.; Mumtaz, A.; Bin Asad, M.H.H.; Hassan, M.H. Caffeic acid phenethyl ester and therapeutic potentials. BioMed Res. Int., 2014, 2014, 1-9.
[http://dx.doi.org/10.1155/2014/145342] [PMID: 24971312]
[20]
Murtaza, G.; Sajjad, A.; Mehmood, Z.; Shah, S.H.; Siddiqi, A.R. Possible molecular targets for therapeutic applications of caffeic acid phenethyl ester in inflammation and cancer. J. Food Drug Anal., 2015, 23(1), 11-18.
[http://dx.doi.org/10.1016/j.jfda.2014.06.001] [PMID: 28911433]
[21]
Naveed, M.; Hejazi, V.; Abbas, M.; Kamboh, A.A.; Khan, G.J.; Shumzaid, M.; Ahmad, F.; Babazadeh, D.; FangFang, X.; Modarresi-Ghazani, F.; WenHua, L.; XiaoHui, Z. Chlorogenic acid (CGA): A pharmacological review and call for further research. Biomed. Pharmacother., 2018, 97, 67-74.
[http://dx.doi.org/10.1016/j.biopha.2017.10.064] [PMID: 29080460]
[22]
Koshovyi, O.; Zagayko, A.; Kolychev, I.; Akhmedov, E.Y.; Komissarenko, A. Phytochemical study of the dry extract from bilberry leaves. Azerbaijan Pharm. Pharmacother. J., 2016, 1, 18-23.
[23]
Shinkovenko, I.L.; Kashpur, N.V.; Ilyina, T.V.; Kovalyova, A.M.; Goryacha, O.V.; Koshovyi, O.M.; Toryanyk, E.L.; Kryvoruchko, O.V. The immunomodulatory activity of the extracts and complexes of biologically active compounds of Galium verum L. herb. Ceska Slov. Farm., 2018, 67(1), 25-29.
[PMID: 30157664]
[24]
Jiang, Y.; Lin, Y.; Hu, Y.J.; Song, X.J.; Pan, H.H.; Zhang, H.J. Caffeoylquinic acid derivatives rich extract from Gnaphalium pensylvanicum willd. Ameliorates hyperuricemia and acute gouty arthritis in animal model. BMC Complement. Altern. Med., 2017, 17(1), 320.
[http://dx.doi.org/10.1186/s12906-017-1834-9] [PMID: 28623927]
[25]
Lee, Y.J.; Jang, Y.N.; Han, Y.M.; Kim, H.M.; Jeong, J.M.; Son, M.J.; Jin, C.B.; Kim, H.J.; Seo, H.S. Caffeoylquinic acid-rich extract of Aster glehni F. Schmidt ameliorates nonalcoholic fatty liver through the regulation of PPARdelta and adiponectin in ApoE KO mice. PPAR Res., 2017, 2017, 1-19.
[http://dx.doi.org/10.1155/2017/3912567] [PMID: 29201040]
[26]
Lenchyk, L.; Ovezgeldiyev, D.; Upyr, D. Phytochemical investigation of bird cherry fruits. Pharm. Lett., 2016, 8(6), 73-76.
[27]
Lenchyk, L.V.; Saidov, N.B. Investigation of phenolic compounds in cherry leaves extract. Res. J. Pharm. and Tech., 2017, 10(12), 4402-4406.
[http://dx.doi.org/10.5958/0974-360X.2017.00811.3]
[28]
Morton, L.W.; Caccetta, R.A-A.; Puddey, I.B.; Croft, K.D. Chemistry and biological effects of dietary phenolic compounds: Relevance to cardiovascular disease. Clin. Exp. Pharmacol. Physiol., 2000, 27(3), 152-159.
[http://dx.doi.org/10.1046/j.1440-1681.2000.03214.x] [PMID: 10744340]
[29]
Kanimozhi, G.; Prasad, N.R. Coffee in Health and Disease Prevention; Vr, P., Ed.; Academic Press: Amsterdam, 2015, pp. 655-661.
[http://dx.doi.org/10.1016/B978-0-12-409517-5.00073-5]
[30]
Popova, M.; Reyes, M.; Le Conte, Y.; Bankova, V. Propolis chemical composition and honeybee resistance against Varroa destructor. Nat. Prod. Res., 2014, 28(11), 788-794.
[http://dx.doi.org/10.1080/14786419.2014.881366] [PMID: 24483289]
[31]
Bankova, V.; Trusheva, B.; Popova, M. Caffeic acid phenethyl ester (CAPE)-natural sources, analytical procedures and synthetic approaches. Dokl. Bulg. Akad. Nauk., 2018, 71(9), 1157-1169.
[http://dx.doi.org/10.7546/CRABS.2018.09.01]
[32]
Kečkeš, S.; Gašić, U.; Veličković, T.Ć.; Milojković-Opsenica, D.; Natić, M.; Tešić, Ž. The determination of phenolic profiles of Serbian unifloral honeys using ultra-high-performance liquid chromatography/high resolution accurate mass spectrometry. Food Chem., 2013, 138(1), 32-40.
[http://dx.doi.org/10.1016/j.foodchem.2012.10.025] [PMID: 23265452]
[33]
Wu, J.; Omene, C.; Karkoszka, J.; Bosland, M.; Eckard, J.; Klein, C.B.; Frenkel, K. Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer. Cancer Lett., 2011, 308(1), 43-53.
[http://dx.doi.org/10.1016/j.canlet.2011.04.012] [PMID: 21570765]
[34]
Chen, H.C.; Chen, J.H.; Chang, C.; Shieh, C.J. Optimization of ultrasound-accelerated synthesis of enzymatic caffeic acid phenethyl ester by response surface methodology. Ultrason. Sonochem., 2011, 18(1), 455-459.
[http://dx.doi.org/10.1016/j.ultsonch.2010.07.018] [PMID: 20797894]
[35]
Kim, H.; Park, C. Enzymatic synthesis of phenethyl ester from phenethyl alcohol with acyl donors. Enzyme Microb. Technol., 2017, 100, 37-44.
[http://dx.doi.org/10.1016/j.enzmictec.2017.02.004] [PMID: 28284310]
[36]
Wang, X.; Pang, J.; Maffucci, J.A.; Pade, D.S.; Newman, R.A.; Kerwin, S.M.; Bowman, P.D.; Stavchansky, S. Pharmacokinetics of caffeic acid phenethyl ester and its catechol-ring fluorinated derivative following intravenous administration to rats. Biopharm. Drug Dispos., 2009, 30(5), 221-228.
[http://dx.doi.org/10.1002/bdd.657] [PMID: 19544289]
[37]
Kleczka, A.; Kubina, R.; Dzik, R.; Jasik, K.; Stojko, J.; Cholewa, K.; Kabała-Dzik, A. Caffeic acid phenethyl ester (CAPE) induced apoptosis in serous ovarian cancer OV7 cells by deregulation of BCL2/BAX genes. Molecules, 2020, 25(15), 3514.
[http://dx.doi.org/10.3390/molecules25153514] [PMID: 32752091]
[38]
Rzepecka-Stojko, A.; Kabała-Dzik, A.; Moździerz, A.; Kubina, R.; Wojtyczka, R.; Stojko, R.; Dziedzic, A.; Jastrzębska-Stojko, Ż.; Jurzak, M.; Buszman, E.; Stojko, J. Caffeic acid phenethyl ester and ethanol extract of propolis induce the complementary cytotoxic effect on triple-negative breast cancer cell lines. Molecules, 2015, 20(5), 9242-9262.
[http://dx.doi.org/10.3390/molecules20059242] [PMID: 26007182]
[39]
Cheng, C.C.; Chi, P.L.; Shen, M.C.; Shu, C.W.; Wann, S.R.; Liu, C.P.; Tseng, C.J.; Huang, W.C. Caffeic acid phenethyl ester rescues pulmonary arterial hypertension through the inhibition of AKT/ERK-dependent PDGF/HIF-1α in vitro and in vivo. Int. J. Mol. Sci., 2019, 20(6), 1468.
[http://dx.doi.org/10.3390/ijms20061468] [PMID: 30909527]
[40]
Yordanov, Y. Caffeic acid phenethyl ester (CAPE): Pharmacodynamics and potential for therapeutic application. Pharmacia, 2019, 66(3), 107-114.
[http://dx.doi.org/10.3897/pharmacia.66.e38573]
[41]
Shen, H.; Yamashita, A.; Nakakoshi, M.; Yokoe, H.; Sudo, M.; Kasai, H.; Tanaka, T.; Fujimoto, Y.; Ikeda, M.; Kato, N.; Sakamoto, N.; Shindo, H.; Maekawa, S.; Enomoto, N.; Tsubuki, M.; Moriishi, K. Inhibitory effects of caffeic acid phenethyl ester derivatives on replication of hepatitis C virus. PLoS One, 2013, 8(12), e82299.
[http://dx.doi.org/10.1371/journal.pone.0082299] [PMID: 24358168]
[42]
Lin, H.P.; Lin, C.Y.; Huo, C.; Hsiao, P.H.; Su, L.C.; Jiang, S.S.; Chan, T.M.; Chang, C.H.; Chen, L.T.; Kung, H.J.; Wang, H.D.; Chuu, C.P. Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1. Oncotarget, 2015, 6(9), 6684-6707.
[http://dx.doi.org/10.18632/oncotarget.3246] [PMID: 25788262]
[43]
Lin, H.P.; Lin, C.Y.; Liu, C.C.; Su, L.C.; Huo, C.; Kuo, Y.Y.; Tseng, J.C.; Hsu, J.M.; Chen, C.K.; Chuu, C.P. Caffeic acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int. J. Mol. Sci., 2013, 14(3), 5264-5283.
[http://dx.doi.org/10.3390/ijms14035264] [PMID: 23466879]
[44]
Motawi, T.K.; Abdelazim, S.A.; Darwish, H.A.; Elbaz, E.M.; Shouman, S.A. Could caffeic acid phenethyl ester expand the antitumor effect of tamoxifen in breast carcinoma? Nutr. Cancer, 2016, 68(3), 435-445.
[http://dx.doi.org/10.1080/01635581.2016.1153669] [PMID: 27007181]
[45]
D’Almeida, R.E.; Alberto, M.R.; Quispe, C.; Schmeda-Hirschmann, G.; Isla, M.I. Antimicrobial phenylpropanoids from the Argentinean highland plant Parastrephia lucida (Meyen) Cabrera. J. Ethnopharmacol., 2012, 142(2), 407-414.
[http://dx.doi.org/10.1016/j.jep.2012.05.010] [PMID: 22735664]
[46]
Jung, W.K.; Lee, D.Y.; Kim, J.H.; Choi, I.; Park, S.G.; Seo, S.K.; Lee, S.W.; Lee, C.M.; Park, Y.M.; Jeon, Y.J.; Lee, C.H.; Jeon, B-T.; Qian, Z-J.; Kim, S-K.; Choi, I-W. Anti-inflammatory activity of caffeic acid phenethyl ester (CAPE) extracted from Rhodiola sacra against lipopolysaccharide-induced inflammatory responses in mice. Process Biochem., 2008, 43(7), 783-787.
[http://dx.doi.org/10.1016/j.procbio.2008.03.004]
[47]
Russo, A.; Longo, R.; Vanella, A. Antioxidant activity of propolis: Role of caffeic acid phenethyl ester and galangin. Fitoterapia, 2002, 73(Suppl. 1), S21-S29.
[http://dx.doi.org/10.1016/S0367-326X(02)00187-9] [PMID: 12495706]
[48]
Iraz, M.; Ozerol, E.; Gulec, M.; Tasdemir, S.; Idiz, N.; Fadillioglu, E.; Naziroglu, M.; Akyol, O. Protective effect of caffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage to liver in rat. Cell Biochem. Funct., 2006, 24(4), 357-361.
[http://dx.doi.org/10.1002/cbf.1232] [PMID: 16437419]
[49]
Nur, G.; Husunet, M.; Guler, I.; Deveci, A.; Koc, E.; Nur, O.; Kilicle, P. The effect of caffeic acid phenethyl ester (CAPE) on hepatic histopathology and oxidative stress in rats treated with malathion. Med. Sci. (Turkey), 2018, 7(0), 604-609.
[http://dx.doi.org/10.5455/medscience.2018.07.8833]
[50]
Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic. Biol. Med., 2010, 49(11), 1603-1616.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.09.006] [PMID: 20840865]
[51]
Bilikova, K.; Popova, M.; Trusheva, B.; Bankova, V. New anti-Paenibacillus larvae substances purified from propolis. Apidologie (Celle), 2013, 44(3), 278-285.
[http://dx.doi.org/10.1007/s13592-012-0178-1]
[52]
Koo, H.J.; Lee, K.R.; Kim, H.S.; Lee, B.M. Detoxification effects of aloe polysaccharide and propolis on the urinary excretion of metabolites in smokers. Food Chem. Toxicol., 2019, 130, 99-108.
[http://dx.doi.org/10.1016/j.fct.2019.05.029] [PMID: 31112706]
[53]
Ishikawa, H.; Goto, M.; Matsuura, N.; Murakami, Y.; Goto, C.; Sakai, T.; Kanazawa, K. A pilot, randomized, placebo-controlled, double-blind phase 0/biomarker study on effect of artepillin C-rich extract of Brazilian propolis in frequent colorectal adenoma polyp patients. J. Am. Coll. Nutr., 2012, 31(5), 327-337.
[http://dx.doi.org/10.1080/07315724.2012.10720434] [PMID: 23529990]
[54]
Altuğ, M.E.; Serarslan, Y.; Bal, R.; Kontaş, T.; Ekici, F.; Melek, I.M.; Aslan, H.; Duman, T. Caffeic acid phenethyl ester protects rabbit brains against permanent focal ischemia by antioxidant action: A biochemical and planimetric study. Brain Res., 2008, 1201, 135-142.
[http://dx.doi.org/10.1016/j.brainres.2008.01.053] [PMID: 18308295]
[55]
Ozer, M.K.; Parlakpinar, H.; Acet, A. Reduction of ischemia–reperfusion induced myocardial infarct size in rats by caffeic acid phenethyl ester (CAPE). Clin. Biochem., 2004, 37(8), 702-705.
[http://dx.doi.org/10.1016/j.clinbiochem.2004.01.012] [PMID: 15302615]
[56]
Amalia, E.; Diantini, A.; Endang Prabandari, E.; Waluyo, D.; Subarnas, A. Caffeic acid phenethyl ester as a DHODH inhibitor and its synergistic anticancer properties in combination with 5-fluorouracil in a breast cancer cell line. J. Exp. Pharmacol., 2022, 14, 243-253.
[http://dx.doi.org/10.2147/JEP.S365159] [PMID: 35910085]
[57]
Fu, Y.K.; Wang, B.J.; Tseng, J.C.; Huang, S.H.; Lin, C.Y.; Kuo, Y.Y.; Hour, T.C.; Chuu, C.P. Combination treatment of docetaxel with caffeic acid phenethyl ester suppresses the survival and the proliferation of docetaxel-resistant prostate cancer cells via induction of apoptosis and metabolism interference. J. Biomed. Sci., 2022, 29(1), 16.
[http://dx.doi.org/10.1186/s12929-022-00797-z] [PMID: 35197069]
[58]
Chang, K.S.; Tsui, K.H.; Hsu, S.Y.; Sung, H.C.; Lin, Y.H.; Hou, C.P.; Yang, P.S.; Chen, C.L.; Feng, T.H.; Juang, H.H. The antitumor effect of caffeic acid phenethyl ester by downregulating mucosa-associated lymphoid tissue 1 via ar/p53/nf-kappab signaling in prostate carcinoma cells. Cancers (Basel), 2022, 14(2), 274.
[http://dx.doi.org/10.3390/cancers14020274] [PMID: 35053438]
[59]
Fraser, S.P.; Hemsley, F.; Djamgoz, M.B.A. Caffeic acid phenethyl ester: Inhibition of metastatic cell behaviours via voltage-gated sodium channel in human breast cancer in vitro. Int. J. Biochem. Cell Biol., 2016, 71, 111-118.
[http://dx.doi.org/10.1016/j.biocel.2015.12.012] [PMID: 26724521]
[60]
Demestre, M.; Messerli, S.M.; Celli, N.; Shahhossini, M.; Kluwe, L.; Mautner, V.; Maruta, H. CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice. Phytother. Res., 2009, 23(2), 226-230.
[http://dx.doi.org/10.1002/ptr.2594] [PMID: 18726924]
[61]
Ozturk, G.; Ginis, Z.; Akyol, S.; Erden, G.; Gurel, A.; Akyol, O. The anticancer mechanism of caffeic acid phenethyl ester (CAPE): Review of melanomas, lung and prostate cancers. Eur. Rev. Med. Pharmacol. Sci., 2012, 16(15), 2064-2068.
[PMID: 23280020]
[62]
Jiang, X.; Xie, H.; Li, C.; You, M.; Zheng, Y.; Li, G.Q.; Chen, X.; Zhang, C.; Hu, F. Chinese propolis inhibits the proliferation of human gastric cancer cells by inducing apoptosis and cell cycle arrest. Evid. Based Complement. Alternat. Med., 2020, 2020, 1-11.
[http://dx.doi.org/10.1155/2020/2743058] [PMID: 32774408]
[63]
Akyol, S.; Ginis, Z.; Armutcu, F.; Ozturk, G.; Yigitoglu, M.R.; Akyol, O. The potential usage of caffeic acid phenethyl ester (CAPE) against chemotherapy-induced and radiotherapy-induced toxicity. Cell Biochem. Funct., 2012, 30(5), 438-443.
[http://dx.doi.org/10.1002/cbf.2817] [PMID: 22431158]
[64]
Cauli, O. Oxidative stress and cognitive alterations induced by cancer chemotherapy drugs: A scoping review. Antioxidants, 2021, 10(7), 1116.
[http://dx.doi.org/10.3390/antiox10071116] [PMID: 34356349]
[65]
Luo, C.; Xu, X.; Wei, X.; Feng, W.; Huang, H.; Liu, H.; Xu, R.; Lin, J.; Han, L.; Zhang, D. Natural medicines for the treatment of fatigue: Bioactive components, pharmacology, and mechanisms. Pharmacol. Res., 2019, 148, 104409.
[http://dx.doi.org/10.1016/j.phrs.2019.104409] [PMID: 31446039]
[66]
Sung, H.C.; Chang, K.S.; Chen, S.T.; Hsu, S.Y.; Lin, Y.H.; Hou, C.P.; Feng, T.H.; Tsui, K.H.; Juang, H.H. Metallothionein 2A with antioxidant and antitumor activity is upregulated by caffeic acid phenethyl ester in human bladder carcinoma cells. Antioxidants, 2022, 11(8), 1509.
[http://dx.doi.org/10.3390/antiox11081509] [PMID: 36009228]
[67]
Gong, Z.; Gao, X.; Yang, Q.; Lun, J.; Xiao, H.; Zhong, J.; Cao, H. Phosphorylation of ERK-dependent NF-κB triggers NLRP3 inflammasome mediated by vimentin in EV71-infected glioblastoma cells. Molecules, 2022, 27(13), 4190.
[http://dx.doi.org/10.3390/molecules27134190] [PMID: 35807435]
[68]
Sucu, B.O.; Koc, E.B.; Savlug Ipek, O.; Mirat, A.; Almas, F.; Guzel, M.A.; Dogan, B.; Uludag, D.; Karakas, N.; Durdagi, S.; Guzel, M. Design and synthesis of novel caffeic acid phenethyl ester (CAPE) derivatives and their biological activity studies in glioblastoma multiforme (GBM) cancer cell lines. J. Mol. Graph. Model., 2022, 113, 108160.
[http://dx.doi.org/10.1016/j.jmgm.2022.108160] [PMID: 35248814]
[69]
Piredda, M.; Facchinetti, G.; Biagioli, V.; Giannarelli, D.; Armento, G.; Tonini, G.; De Marinis, M.G. Propolis in the prevention of oral mucositis in breast cancer patients receiving adjuvant chemotherapy: A pilot randomised controlled trial. Eur. J. Cancer Care (Engl.), 2017, 26(6), e12757.
[http://dx.doi.org/10.1111/ecc.12757] [PMID: 28840622]
[70]
Sforcin, J.M. Propolis and the immune system: A review. J. Ethnopharmacol., 2007, 113(1), 1-14.
[http://dx.doi.org/10.1016/j.jep.2007.05.012] [PMID: 17580109]
[71]
Marucci, L.; Farneti, A.; Di Ridolfi, P.; Pinnaro, P.; Pellini, R.; Giannarelli, D.; Vici, P.; Conte, M.; Landoni, V.; Sanguineti, G. Double-blind randomized phase III study comparing a mixture of natural agents versus placebo in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer. Head Neck, 2017, 39(9), 1761-1769.
[http://dx.doi.org/10.1002/hed.24832] [PMID: 28560780]
[72]
Randomized double blind placebo controlled trial of propolis for oral mucositis in patients receiving chemotherapy for head and neck cancer. Asian Pac. J. Cancer Prev., 2016, 17(7), 3611-3614.
[PMID: 27510017]
[73]
Noronha, V.; Araujo, G.; Gomes, R.; Iwanaga, S.; Barbosa, M.; Abdo, E.; e Ferreira, E.; Viana, A.; Souza, A.; Abreu, S.; Santos, V. Mucoadhesive propolis gel for prevention of radiation-induced oral mucositis. Curr. Clin. Pharmacol., 2014, 9(4), 359-364.
[http://dx.doi.org/10.2174/1574884709666140205210051] [PMID: 24502424]
[74]
Abdulrhman, M.; Samir Elbarbary, N.; Ahmed Amin, D.; Saeid Ebrahim, R. Honey and a mixture of honey, beeswax, and olive oil-propolis extract in treatment of chemotherapy-induced oral mucositis: A randomized controlled pilot study. Pediatr. Hematol. Oncol., 2012, 29(3), 285-292.
[http://dx.doi.org/10.3109/08880018.2012.669026] [PMID: 22475306]
[75]
Tomaževič, T.; Jazbec, J. A double blind randomised placebo controlled study of propolis (bee glue) effectiveness in the treatment of severe oral mucositis in chemotherapy treated children. Complement. Ther. Med., 2013, 21(4), 306-312.
[http://dx.doi.org/10.1016/j.ctim.2013.04.002] [PMID: 23876561]
[76]
Shin, S.H.; Lee, S.R.; Lee, E.; Kim, K.H.; Byun, S. Caffeic acid phenethyl ester from the twigs of Cinnamomum cassia inhibits malignant cell transformation by inducing c-Fos degradation. J. Nat. Prod., 2017, 80(7), 2124-2130.
[http://dx.doi.org/10.1021/acs.jnatprod.7b00433] [PMID: 28682072]
[77]
Erdis, E. Can CAPE be used as ideal antitumor agent “safely”? Eur. Rev. Med. Pharmacol. Sci., 2013, 17(4), 567.
[PMID: 23467961]
[78]
Omene, C.; Kalac, M.; Wu, J.; Marchi, E.; Frenkel, K.; O’Connor, O.A. Propolis and its active component, caffeic acid phenethyl ester (CAPE), modulate breast cancer therapeutic targets via an epigenetically mediated mechanism of action. J. Cancer Sci. Ther., 2013, 5(10), 334-342.
[PMID: 24466386]
[79]
Omene, C.O.; Wu, J.; Frenkel, K. Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells. Invest. New Drugs, 2012, 30(4), 1279-1288.
[http://dx.doi.org/10.1007/s10637-011-9667-8] [PMID: 21537887]
[80]
Kosova, F.; Kurt, F.O.; Olmez, E.; Tuğlu, I.; Arı, Z. Effects of caffeic acid phenethyl ester on matrix molecules and angiogenetic and anti-angiogenetic factors in gastric cancer cells cultured on different substrates. Biotech. Histochem., 2016, 91(1), 38-47.
[http://dx.doi.org/10.3109/10520295.2015.1072769] [PMID: 26523612]
[81]
Kim, H.G.; Han, E.H.; Im, J.H.; Lee, E.J.; Jin, S.W.; Jeong, H.G. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α. Biochem. Biophys. Res. Commun., 2015, 465(3), 562-568.
[http://dx.doi.org/10.1016/j.bbrc.2015.08.060] [PMID: 26296470]
[82]
Kuo, Y.Y.; Jim, W.T.; Su, L.C.; Chung, C.J.; Lin, C.Y.; Huo, C.; Tseng, J.C.; Huang, S.H.; Lai, C.J.; Chen, B.C.; Wang, B.J.; Chan, T.M.; Lin, H.P.; Chang, W.S.; Chang, C.R.; Chuu, C.P. Caffeic acid phenethyl ester is a potential therapeutic agent for oral cancer. Int. J. Mol. Sci., 2015, 16(12), 10748-10766.
[http://dx.doi.org/10.3390/ijms160510748] [PMID: 25984601]
[83]
Balkhi, H.M.; Gul, T.; Sana, S.; Haq, E. Potential synergism of caffeic acid phenethyl ester and dasatinib in c6 glioma cell model: Adumbrating the molecular mechanism. Brain Disord. Ther., 2018, 7(2), 2.
[http://dx.doi.org/10.4172/2168-975X.1000245]
[84]
Budisan, L.; Gulei, D.; Jurj, A.; Braicu, C.; Zanoaga, O.; Cojocneanu, R.; Pop, L.; Raduly, L.; Barbat, A.; Moldovan, A.; Moldovan, C.; Tigu, A.; Ionescu, C.; Atanasov, A.; Irimie, A.; Berindan-Neagoe, I. Inhibitory effect of cape and kaempferol in colon cancer cell lines—possible implications in new therapeutic strategies. Int. J. Mol. Sci., 2019, 20(5), 1199.
[http://dx.doi.org/10.3390/ijms20051199] [PMID: 30857282]
[85]
Chung, L.C.; Chiang, K.C.; Feng, T.H.; Chang, K.S.; Chuang, S.T.; Chen, Y.J.; Tsui, K.H.; Lee, J.C.; Juang, H.H. Caffeic acid phenethyl ester upregulates N-myc downstream regulated gene 1 via ERK pathway to inhibit human oral cancer cell growth in vitro and in vivo. Mol. Nutr. Food Res., 2017, 61(9), 1600842.
[http://dx.doi.org/10.1002/mnfr.201600842] [PMID: 28181403]
[86]
Dziedzic, A.; Kubina, R.; Kabała-Dzik, A.; Tanasiewicz, M. Induction of cell cycle arrest and apoptotic response of head and neck squamous carcinoma cells (Detroit 562) by caffeic acid and caffeic acid phenethyl ester derivative. Evid. Based Complement. Alternat. Med., 2017, 2017, 1-10.
[http://dx.doi.org/10.1155/2017/6793456] [PMID: 28167973]
[87]
Chang, H.; Wang, Y.; Yin, X.; Liu, X.; Xuan, H. Ethanol extract of propolis and its constituent caffeic acid phenethyl ester inhibit breast cancer cells proliferation in inflammatory microenvironment by inhibiting TLR4 signal pathway and inducing apoptosis and autophagy. BMC Complement. Altern. Med., 2017, 17(1), 471.
[http://dx.doi.org/10.1186/s12906-017-1984-9] [PMID: 28950845]
[88]
Imai, M.; Yokoe, H.; Tsubuki, M.; Takahashi, N. Growth inhibition of human breast and prostate cancer cells by cinnamic acid derivatives and their mechanism of action. Biol. Pharm. Bull., 2019, 42(7), 1134-1139.
[http://dx.doi.org/10.1248/bpb.b18-01002] [PMID: 30982786]
[89]
Kabała-Dzik, A.; Rzepecka-Stojko, A.; Kubina, R.; Wojtyczka, R.D.; Buszman, E.; Stojko, J. Caffeic acid versus caffeic acid phenethyl ester in the treatment of breast cancer MCF-7 cells: Migration rate inhibition. Integr. Cancer Ther., 2018, 17(4), 1247-1259.
[http://dx.doi.org/10.1177/1534735418801521] [PMID: 30246565]
[90]
Chiang, K.C.; Yang, S.W.; Chang, K.P.; Feng, T.H.; Chang, K.S.; Tsui, K.H.; Shin, Y.S.; Chen, C.C.; Chao, M.; Juang, H.H. Caffeic acid phenethyl ester induces N-myc downstream regulated gene 1 to inhibit cell proliferation and invasion of human nasopharyngeal cancer cells. Int. J. Mol. Sci., 2018, 19(5), 1397.
[http://dx.doi.org/10.3390/ijms19051397] [PMID: 29738439]
[91]
Liang, Y.; Feng, G.; Wu, L.; Zhong, S.; Gao, X.; Tong, Y.; Cui, W.; Qin, Y.; Xu, W.; Xiao, X.; Zhang, Z.; Huang, G.; Zhou, X. Caffeic acid phenethyl ester suppressed growth and metastasis of nasopharyngeal carcinoma cells by inactivating the NF-κB pathway. Drug Des. Devel. Ther., 2019, 13, 1335-1345.
[http://dx.doi.org/10.2147/DDDT.S199182] [PMID: 31118570]
[92]
Liu, G.L.; Han, N.Z.; Liu, S.S. Caffeic acid phenethyl ester inhibits the progression of ovarian cancer by regulating NF-κB signaling. Biomed. Pharmacother., 2018, 99, 825-831.
[http://dx.doi.org/10.1016/j.biopha.2018.01.129] [PMID: 29710481]
[93]
Khoram, N.M.; Bigdeli, B.; Nikoofar, A.; Goliaei, B. Caffeic acid phenethyl ester increases radiosensitivity of estrogen receptor-positive and-negative breast cancer cells by prolonging radiation-induced DNA damage. J. Breast Cancer, 2016, 19(1), 18-25.
[http://dx.doi.org/10.4048/jbc.2016.19.1.18] [PMID: 27066092]
[94]
Omene, C.; Patel, M.; Karagoz, K.; Gatza, M.L.; Barcellos-Hoff, M.H. Abstract P4-07-03: Immunomodulation of triple negative breast cancer by caffeic acid phenethyl ester (CAPE). Cancer Res., 2019, 79(4_Supplement), P4-07-03.
[http://dx.doi.org/10.1158/1538-7445.SABCS18-P4-07-03]
[95]
Onori, P.; DeMorrow, S.; Gaudio, E.; Franchitto, A.; Mancinelli, R.; Venter, J.; Kopriva, S.; Ueno, Y.; Alvaro, D.; Savage, J.; Alpini, G.; Francis, H. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-κB and induction of apoptosis. Int. J. Cancer, 2009, 125(3), 565-576.
[http://dx.doi.org/10.1002/ijc.24271] [PMID: 19358267]
[96]
Fırat, F.; Özgül, M.; Türköz Uluer, E.; Inan, S. Effects of caffeic acid phenethyl ester (CAPE) on angiogenesis, apoptosis and oxidatıve stress ın various cancer cell lines. Biotech. Histochem., 2019, 94(7), 491-497.
[http://dx.doi.org/10.1080/10520295.2019.1589574] [PMID: 30991851]
[97]
Kurauchi, Y.; Hisatsune, A.; Isohama, Y.; Mishima, S.; Katsuki, H. Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor. Br. J. Pharmacol., 2012, 166(3), 1151-1168.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01833.x] [PMID: 22224485]
[98]
Wadhwa, R.; Nigam, N.; Bhargava, P.; Dhanjal, J.K.; Goyal, S.; Grover, A.; Sundar, D.; Ishida, Y.; Terao, K.; Kaul, S.C. Molecular characterization and enhancement of anticancer activity of caffeic acid phenethyl ester by γ cyclodextrin. J. Cancer, 2016, 7(13), 1755-1771.
[http://dx.doi.org/10.7150/jca.15170] [PMID: 27698914]
[99]
Wu, W.; Gao, F.; Song, X.H.F.; Zhao, Y.; Xu, M.; Zhang, X.; Yang, Z.; Yang, Z. Caffeic Acid Phenethyl Ester (CAPE) mediated decrease in metastasis of colon cancer cells: An in vitro and in vivo study. Afr. J. Tradit. Complement. Altern. Med., 2017, 14(5), 63-71.
[http://dx.doi.org/10.21010/ajtcam.v14i5.9]
[100]
Ishida, Y.; Gao, R.; Shah, N.; Bhargava, P.; Furune, T.; Kaul, S.C.; Terao, K.; Wadhwa, R. Anticancer activity in honeybee propolis: Functional insights to the role of caffeic acid phenethyl ester and its complex with γ-cyclodextrin. Integr. Cancer Ther., 2018, 17(3), 867-873.
[http://dx.doi.org/10.1177/1534735417753545] [PMID: 29390900]
[101]
Pattingre, S.; Levine, B. Bcl-2 inhibition of autophagy: A new route to cancer? Cancer Res., 2006, 66(6), 2885-2888.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-4412] [PMID: 16540632]
[102]
Gong, C.; Bauvy, C.; Tonelli, G.; Yue, W.; Deloménie, C.; Nicolas, V.; Zhu, Y.; Domergue, V.; Marin-Esteban, V.; Tharinger, H.; Delbos, L.; Gary-Gouy, H.; Morel, A-P.; Ghavami, S.; Song, E.; Codogno, P.; Mehrpour, M. Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene, 2013, 32(18), 2261-2272, 1-11.
[http://dx.doi.org/10.1038/onc.2012.252] [PMID: 22733132]
[103]
Gong, C.; Song, E.; Codogno, P.; Mehrpour, M. The roles of BECN1 and autophagy in cancer are context dependent. Autophagy, 2012, 8(12), 1853-1855.
[http://dx.doi.org/10.4161/auto.21996] [PMID: 22960473]
[104]
Hui, B.; Shi, Y.H.; Ding, Z.B.; Zhou, J.; Gu, C.Y.; Peng, Y.F.; Yang, H.; Liu, W.R.; Shi, G.M.; Fan, J. Proteasome inhibitor interacts synergistically with autophagy inhibitor to suppress proliferation and induce apoptosis in hepatocellular carcinoma. Cancer, 2012, 118(22), 5560-5571.
[http://dx.doi.org/10.1002/cncr.27586] [PMID: 22517429]
[105]
He, Y.J.; Li, W-L.; Liu, B-H.; Dong, H.; Mou, Z-R.; Wu, Y-Z. Identification of differential proteins in colorectal cancer cells treated with caffeic acid phenethyl ester. World J. Gastroenterol., 2014, 20(33), 11840-11849.
[http://dx.doi.org/10.3748/wjg.v20.i33.11840] [PMID: 25206290]
[106]
Gavilán, E.; Giráldez, S.; Sánchez-Aguayo, I.; Romero, F.; Ruano, D.; Daza, P. Breast cancer cell line MCF7 escapes from G1/S arrest induced by proteasome inhibition through a GSK-3β dependent mechanism. Sci. Rep., 2015, 5(1), 10027.
[http://dx.doi.org/10.1038/srep10027] [PMID: 25941117]
[107]
Francielli de Oliveira, P.; Lima, I.M.S.; Monteiro Neto, M.A.B.; Bastos, J.K.; da Silva Filho, A.A.; Tavares, D.C. Evaluation of genotoxicity and antigenotoxicity of artepillin C in V79 cells by the comet and micronucleus assays. Nutr. Cancer, 2013, 65(7), 1098-1103.
[http://dx.doi.org/10.1080/01635581.2013.815233] [PMID: 23915392]
[108]
Maistro, E.L.; Angeli, J.P.F.; Andrade, S.F.; Mantovani, M.S. In vitro genotoxicity assessment of caffeic, cinnamic and ferulic acids. Genet. Mol. Res., 2011, 10(2), 1130-1140.
[http://dx.doi.org/10.4238/vol10-2gmr1278] [PMID: 21710465]
[109]
Tan, K.W.; Li, Y.; Paxton, J.W.; Birch, N.P.; Scheepens, A. Identification of novel dietary phytochemicals inhibiting the efflux transporter breast cancer resistance protein (BCRP/ABCG2). Food Chem., 2013, 138(4), 2267-2274.
[http://dx.doi.org/10.1016/j.foodchem.2012.12.021] [PMID: 23497885]
[110]
Gao, M.; Zhang, W.; Liu, Q.; Hu, J.; Liu, G.; Du, G. Pinocembrin prevents glutamate-induced apoptosis in SH-SY5Y neuronal cells via decrease of bax/bcl-2 ratio. Eur. J. Pharmacol., 2008, 591(1-3), 73-79.
[http://dx.doi.org/10.1016/j.ejphar.2008.06.071] [PMID: 18625218]
[111]
Borrelli, F.; Izzo, A.A.; Di Carlo, G.; Maffia, P.; Russo, A.; Maiello, F.M.; Capasso, F.; Mascolo, N. Effect of a propolis extract and caffeic acid phenethyl ester on formation of aberrant crypt foci and tumors in the rat colon. Fitoterapia, 2002, 73(Suppl. 1), S38-S43.
[http://dx.doi.org/10.1016/S0367-326X(02)00189-2] [PMID: 12495708]
[112]
Davoodi, S.H.; Yousefinejad, V.; Ghaderi, B.; Akbari, M.E.; Darvishi, S.; Mehrabi, Y.; Darvishi, N. Oral propolis, nutritional status and quality of life with chemotherapy for breast cancer: A randomized, double-blind clinical trial. Nutr. Cancer, 2022, 74(6), 2029-2037.
[http://dx.doi.org/10.1080/01635581.2021.1988118] [PMID: 34622721]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy