Beer, the most popular beverage containing hops, is also frequently consumed by cancer patients. Moreover, non-alcoholic beer, owing to its nutritional value and high content of biological active compounds, is sometimes recommended to patients by oncologists. However, the potential benefits and negatives have to date not been sufficiently evaluated. The present study was designed to examine the effects of four main hop-derived prenylflavonoids on the viability, reactive oxygen species (ROS) formation, activity of caspases, and efficiency of the chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (OxPt) and irinotecan (IRI) in colorectal cancer cell lines SW480, SW620 and CaCo-2. All the prenylflavonoids exerted substantial antiproliferative effects in all cell lines, with xanthohumol being the most effective (IC50 ranging from 3.6 to 7.3 µM). Isoxanthohumol increased ROS formation and the activity of caspases-3/7, but 6-prenylnaringenin and 8-prenylnaringenin exerted antioxidant properties. As 6-prenylnaringenin acted synergistically with IRI, its potential in combination therapy deserves further study. However, other prenylflavonoids acted antagonistically with all chemotherapeutics at least in one cell line. Therefore, consumption of beer during chemotherapy with 5-FU, OxPt and IRI should be avoided, as the prenylflavonoids in beer could decrease the efficacy of the treatment.

Faculty of Medicine and Dentistry Palacký University Hněvotínská 3 775 15 Olomouc Czech Republic

Faculty of Pharmacy in Hradec Králové Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

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Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015;136:E359–E386. doi: 10.1002/ijc.29210. PubMed DOI

Sag A.A., Selcukbiricik F., Mandel N.M. Evidence-based medical oncology and interventional radiology paradigms for liver-dominant colorectal cancer metastases. World J. Gastroenterol. 2016;22:3127–3149. doi: 10.3748/wjg.v22.i11.3127. PubMed DOI PMC

Wilson T.R., Johnston P.G., Longley D.B. Anti-apoptotic mechanisms of drug resistance in cancer. Curr. Cancer Drug Targets. 2009;9:307–319. doi: 10.2174/156800909788166547. PubMed DOI

Hammond W.A., Swaika A., Mody K. Pharmacologic resistance in colorectal cancer: A review. Ther. Adv. Med. Oncol. 2016;8:57–84. doi: 10.1177/1758834015614530. PubMed DOI PMC

Prochazkova D., Bousova I., Wilhelmova N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011;82:513–523. doi: 10.1016/j.fitote.2011.01.018. PubMed DOI

Rossi M., Bosetti C., Negri E., Lagiou P., La Vecchia C. Flavonoids, proanthocyanidins, and cancer risk: A network of case-control studies from Italy. Nutr. Cancer. 2010;62:871–877. doi: 10.1080/01635581.2010.509534. PubMed DOI

Miranda C.L., Stevens J.F., Ivanov V., McCall M., Frei B., Deinzer M.L., Buhler D.R. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J. Agric. Food Chem. 2000;48:3876–3884. doi: 10.1021/jf0002995. PubMed DOI

Gerhauser C. Broad spectrum anti-infective potential of xanthohumol from hop (Humulus lupulus L.) in comparison with activities of other hop constituents and xanthohumol metabolites. Mol. Nutr. Food Res. 2005;49:827–831. doi: 10.1002/mnfr.200500091. PubMed DOI

Legette L.L., Luna A.Y., Reed R.L., Miranda C.L., Bobe G., Proteau R.R., Stevens J.F. Xanthohumol lowers body weight and fasting plasma glucose in obese male Zucker fa/fa rats. Phytochemistry. 2013;91:236–241. doi: 10.1016/j.phytochem.2012.04.018. PubMed DOI

Dorn C., Massinger S., Wuzik A., Heilmann J., Hellerbrand C. Xanthohumol suppresses inflammatory response to warm ischemia-reperfusion induced liver injury. Exp. Mol. Pathol. 2013;94:10–16. doi: 10.1016/j.yexmp.2012.05.003. PubMed DOI

Erkkola R., Vervarcke S., Vansteelandt S., Rompotti P., De Keukeleire D., Heyerick A. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine. 2010;17:389–396. doi: 10.1016/j.phymed.2010.01.007. PubMed DOI

Pan L., Becker H., Gerhauser C. Xanthohumol induces apoptosis in cultured 40-16 human colon cancer cells by activation of the death receptor- and mitochondrial pathway. Mol. Nutr. Food Res. 2005;49:837–843. doi: 10.1002/mnfr.200500065. PubMed DOI

Sun Z., Zhou C., Liu F., Zhang W., Chen J., Pan Y., Ma L., Liu Q., Du Y., Yang J., et al. Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway in vivo and in vitro. Oncol. Lett. 2018;15:908–916. doi: 10.3892/ol.2017.7434. PubMed DOI PMC

Festa M., Capasso A., D’Acunto C.W., Masullo M., Rossi A.G., Pizza C., Piacente S. Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways. J. Nat. Prod. 2011;74:2505–2513. doi: 10.1021/np200390x. PubMed DOI

Saito K., Matsuo Y., Imafuji H., Okubo T., Maeda Y., Sato T., Shamoto T., Tsuboi K., Morimoto M., Takahashi H., et al. Xanthohumol inhibits angiogenesis by suppressing nuclear factor-kappaB activation in pancreatic cancer. Cancer Sci. 2018;109:132–140. doi: 10.1111/cas.13441. PubMed DOI PMC

Krajnovic T., Kaluderovic G.N., Wessjohann L.A., Mijatovic S., Maksimovic-Ivanic D. Versatile antitumor potential of isoxanthohumol: Enhancement of paclitaxel activity in vivo. Pharmacol. Res. 2016;105:62–73. doi: 10.1016/j.phrs.2016.01.011. PubMed DOI

Gerhauser C. Beer constituents as potential cancer chemopreventive agents. Eur. J. Cancer. 2005;41:1941–1954. doi: 10.1016/j.ejca.2005.04.012. PubMed DOI

Stevens J.F., Page J.E. Xanthohumol and related prenylflavonoids from hops and beer: To your good health! Phytochemistry. 2004;65:1317–1330. doi: 10.1016/j.phytochem.2004.04.025. PubMed DOI

Galadari S., Rahman A., Pallichankandy S., Thayyullathil F. Reactive oxygen species and cancer paradox: To promote or to suppress? Free Radic. Biol. Med. 2017;104:144–164. doi: 10.1016/j.freeradbiomed.2017.01.004. PubMed DOI

Chou T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 2006;58:621–681. doi: 10.1124/pr.58.3.10. PubMed DOI

Plazar J., Zegura B., Lah T.T., Filipic M. Protective effects of xanthohumol against the genotoxicity of benzo(a)pyrene (BaP), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and tert-butyl hydroperoxide (t-BOOH) in HepG2 human hepatoma cells. Mutat. Res. 2007;632:1–8. doi: 10.1016/j.mrgentox.2007.03.013. PubMed DOI

Yu L., Zhang F., Hu Z., Ding H., Tang H., Ma Z., Zhao X. Novel prenylated bichalcone and chalcone from Humulus lupulus and their quinone reductase induction activities. Fitoterapia. 2014;93:115–120. doi: 10.1016/j.fitote.2013.12.019. PubMed DOI

Dietz B.M., Kang Y.H., Liu G., Eggler A.L., Yao P., Chadwick L.R., Pauli G.F., Farnsworth N.R., Mesecar A.D., van Breemen R.B., et al. Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase. Chem. Res. Toxicol. 2005;18:1296–1305. doi: 10.1021/tx050058x. PubMed DOI PMC

Jongthawin J., Techasen A., Loilome W., Yongvanit P., Namwat N. Anti-inflammatory agents suppress the prostaglandin E2 production and migration ability of cholangiocarcinoma cell lines. Asian Pac. J. Cancer Prev. 2012;13:47–51. PubMed

Guo D., Zhang B., Liu S., Jin M. Xanthohumol induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI3K/Akt/mTOR-kinase in human gastric cancer cells. Biomed. Pharmacother. 2018;106:1300–1306. doi: 10.1016/j.biopha.2018.06.166. PubMed DOI

Hudcova T., Bryndova J., Fialova K., Fiala J., Karabin M., Jelinek L., Dostalek P. Antiproliferative effects of prenylflavonoids from hops on human colon cancer cell lines. J. Inst. Brew. 2014;120:225–230. doi: 10.1002/jib.139. DOI

Bartmanska A., Tronina T., Poplonski J., Milczarek M., Filip-Psurska B., Wietrzyk J. Highly Cancer Selective Antiproliferative Activity of Natural Prenylated Flavonoids. Molecules. 2018;23:2922. doi: 10.3390/molecules23112922. PubMed DOI PMC

Stompor M., Uram L., Podgorski R. In Vitro Effect of 8-Prenylnaringenin and Naringenin on Fibroblasts and Glioblastoma Cells-Cellular Accumulation and Cytotoxicity. Molecules. 2017;22:1092. doi: 10.3390/molecules22071092. PubMed DOI PMC

Angelis I.D., Turco L. Caco-2 cells as a model for intestinal absorption. Curr. Protoc. Toxicol. 2011;47 doi: 10.1002/0471140856.tx2006s47. PubMed DOI

Strathmann J., Klimo K., Sauer S.W., Okun J.G., Prehn J.H., Gerhauser C. Xanthohumol-induced transient superoxide anion radical formation triggers cancer cells into apoptosis via a mitochondria-mediated mechanism. FASEB J. 2010;24:2938–2950. doi: 10.1096/fj.10-155846. PubMed DOI

Blanquer-Rossello M.M., Oliver J., Valle A., Roca P. Effect of xanthohumol and 8-prenylnaringenin on MCF-7 breast cancer cells oxidative stress and mitochondrial complexes expression. J. Cell. Biochem. 2013;114:2785–2794. doi: 10.1002/jcb.24627. PubMed DOI

Yang J.Y., Della-Fera M.A., Rayalam S., Baile C.A. Effect of xanthohumol and isoxanthohumol on 3T3-L1 cell apoptosis and adipogenesis. Apoptosis. 2007;12:1953–1963. doi: 10.1007/s10495-007-0130-4. PubMed DOI

Brunelli E., Minassi A., Appendino G., Moro L. 8-Prenylnaringenin, inhibits estrogen receptor-alpha mediated cell growth and induces apoptosis in MCF-7 breast cancer cells. J. Steroid Biochem. Mol. Biol. 2007;107:140–148. doi: 10.1016/j.jsbmb.2007.04.003. PubMed DOI

Totta P., Acconcia F., Leone S., Cardillo I., Marino M. Mechanisms of naringenin-induced apoptotic cascade in cancer cells: Involvement of estrogen receptor alpha and beta signalling. IUBMB Life. 2004;56:491–499. doi: 10.1080/15216540400010792. PubMed DOI

Nguyen-Vu T., Wang J., Mesmar F., Mukhopadhyay S., Saxena A., McCollum C.W., Gustafsson J.A., Bondesson M., Williams C. Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205—PROX1 mechanism. Oncotarget. 2016;7:42159–42171. doi: 10.18632/oncotarget.9895. PubMed DOI PMC

Bayat Mokhtari R., Homayouni T.S., Baluch N., Morgatskaya E., Kumar S., Das B., Yeger H. Combination therapy in combating cancer. Oncotarget. 2017;8:38022–38043. doi: 10.18632/oncotarget.16723. PubMed DOI PMC

Zhang F.Y., Du G.J., Zhang L., Zhang C.L., Lu W.L., Liang W. Naringenin enhances the anti-tumor effect of doxorubicin through selectively inhibiting the activity of multidrug resistance-associated proteins but not P-glycoprotein. Pharm. Res. 2009;26:914–925. doi: 10.1007/s11095-008-9793-y. PubMed DOI

Fu Y., Yang G., Zhu F., Peng C., Li W., Li H., Kim H.G., Bode A.M., Dong Z., Dong Z. Antioxidants decrease the apoptotic effect of 5-Fu in colon cancer by regulating Src-dependent caspase-7 phosphorylation. Cell Death Dis. 2014;5:e983. doi: 10.1038/cddis.2013.509. PubMed DOI PMC

Huang Y.F., Zhu D.J., Chen X.W., Chen Q.K., Luo Z.T., Liu C.C., Wang G.X., Zhang W.J., Liao N.Z. Curcumin enhances the effects of irinotecan on colorectal cancer cells through the generation of reactive oxygen species and activation of the endoplasmic reticulum stress pathway. Oncotarget. 2017;8:40264–40275. doi: 10.18632/oncotarget.16828. PubMed DOI PMC

Mhaidat N.M., Bouklihacene M., Thorne R.F. 5-Fluorouracil-induced apoptosis in colorectal cancer cells is caspase-9-dependent and mediated by activation of protein kinase C-delta. Oncol. Lett. 2014;8:699–704. doi: 10.3892/ol.2014.2211. PubMed DOI PMC

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