Chrysin-Enhanced Cytotoxicity of 5-Fluorouracil-Based Chemotherapy for Colorectal Cancer in Mice
Investigating its Effects on Cyclooxygenase-2 Expression
DOI:
https://doi.org/10.1590/s2175-979020202e19381Keywords:
Colon cancer, Combination treatment, Chrysin, Cyclooxygenase-2Abstract
5-fluorouracil (5-FU) has been recognized as an effective medication used to treat colorectal cancer (CRC); however, its administration is facing limitations due to some complications reported. It is also generally accepted that combination therapy is among strategies to improve chemotherapy efficiency. Therefore, chrysin, with its anticancer effects, in combination with 5-FU was investigated in the present study. Azoxymethane (AOM) as a carcinogenic substance along with dextran sodium sulfate (DSS) was additionally utilized to induce CRC in mice. The anticancer effects of chrysin were then evaluated using aberrant crypt foci (ACF) counting and percentage of pathologic lesions in epithelial tissues from distal colon. In this study, cyclooxygenase (COX-2) protein expression was correspondingly explored through immunohistochemistry (IHC). The results revealed that chrysin alone or in combination with 5-FU could decrease ACF counting and percentage of pathologic lesions in comparison with AOM (p<0.05). Moreover, the combination of chrysin (at a dose of 50 mg/kg) with 5-FU reduced COX-2 expression compared with 5-FU alone (p<0.001) or 5-FU in combination with chrysin at a dose of 100 mg/kg (p<0.05). Furthermore, the combined chrysin boosted 5-FU efficiency, so it was suggested as an auxiliary therapy for CRC.
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Fantini M, Benvenuto M, Masuelli L, Frajese GV, Tresoldi I, Modesti A, et al. In vitro and in vivo antitumoral effects of combinations of polyphenols, or polyphenols and anticancer drugs: perspectives on cancer treatment. Int J Mol Sci. 2015;16(5):9236-9282.
Gao AM, Ke ZP, Shi F, Sun GC, Chen H. Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway. Chem Biol Interact. 2013;206(1):100-108.
Harris GK, Qian Y, Leonard SS, Sbarra DC, Shi X. Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E2 formation in RAW 264.7 cells. J Nutr. 2006;136(6):1517-1521.
Harris RE. Cyclooxygenase-2 (cox-2) andtheinflammogenesis of cancer. Subcell Biochem. 2007;42:93-126.
Khan MS, Devaraj H, Devaraj N. Chrysin abrogates early hepatocarcinogenesis and induces apoptosis in N-nitrosodiethylamine-induced preneoplastic nodules in rats. Toxicol Appl Pharmacol. 2011;251(1):85-94.
Li J, Wang X, Hou J, Huang Y, Zhang Y, Xu W. Enhanced anticancer activity of 5-FU in combination with Bestatin: Evidence in human tumor-derived cell lines and an H22 tumor-bearing mouse. Drug Discov Ther. 2015a;9(1):45-52.
Li X-W, Wang X-M, Li S, Yang J-R. Effects of chrysin (5, 7-dihydroxyflavone) on vascular remodeling in hypoxia- induced pulmonary hypertension in rats. Chin Med. 2015b;10(1):4.
Li X, Huang JM, Wang JN, Xiong XK, Yang XF, Zou F. Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53. Chem Biol Interact . 2015c;232:12-20.
Liang YC, Tsai SH, Tsai DC, Lin-Shiau SY, Lin JK. Suppression of inducible cyclooxygenase and nitric oxide synthase through activation of peroxisome proliferator- activated receptor-gamma by flavonoids in mouse macrophages. FEBS Lett. 2001;496(1):12-18.
Lim HK, Kim KM, Jeong SY, Choi EK, Jung J. Chrysin Increases the Therapeutic Efficacy of Docetaxel and Mitigates Docetaxel-Induced Edema. Integr Cancer Ther. 2017;16(4):496-504.
Lin YM, Chen CI, Hsiang YP, Hsu YC, Cheng KC, Chien PH, et al. Chrysin Attenuates Cell Viability of Human Colorectal Cancer Cells through Autophagy Induction Unlike 5-Fluorouracil/Oxaliplatin. Int J Mol Sci . 2018;19(6):1763
Loomans-Kropp HA, Umar A. Increasing incidence of colorectal cancer in young adults. J Cancer Epidemiol. 2019;2019:9841295.
Miyoshi N, Nagasawa T, Mabuchi R, Yasui Y, Wakabayashi K, Tanaka T, et al. Chemoprevention of azoxymethane/ dextran sodium sulfate-induced mouse colon carcinogenesis by freeze-dried yam sanyaku and its constituent diosgenin. Cancer Prev Res (Phila). 2011;4(6):924-934.
Murad AM, Petroianu A, Guimaraes RC, Aragao BC, Cabral LO, Scalabrini-Neto AO. Phase II trial of the combination of paclitaxel and 5-fluorouracil in the treatment of advanced gastric cancer: a novel, safe, and effective regimen. Am J Clin Oncol. 1999;22(6):580-586.
Perse M, Cerar A. Morphological and molecular alterations in 1,2 dimethylhydrazine and azoxymethane induced colon carcinogenesis in rats. J Biomed Biotechnol. 2011;2011(473964.
Rashid S, Ali N, Nafees S, Hasan SK, Sultana S. Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats. Food Chem Toxicol. 2014;66:185-193.
Ren SZ, Wang ZC, Zhu XH, Zhu D, Li Z, Shen FQ, et al. Design and biological evaluation of novel hybrids of 1, 5-diarylpyrazole and Chrysin for selective COX-2 inhibition. Bioorg Med Chem. 2018;26(14):4264-4275.
Sequetto PL, Oliveira TT, Soares IA, Maldonado IR, Mello VJ, Pizziolo VR, et al. The flavonoid chrysin attenuates colorectal pathological remodeling reducing the number and severity of pre-neoplastic lesions in rats exposed to the carcinogen 1,2-dimethylhydrazine. Cell Tissue Res. 2013;352(2):327-339.
Shakibaei M, Mobasheri A, Lueders C, Busch F, Shayan P, Goel A. Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-kappaB and Src protein kinase signaling pathways. PLoS One. 2013;8(2):e57218.
Sharma RA, Dalgleish AG, Steward WP, O’Byrne KJ. Angiogenesis and the immune response as targets for the prevention and treatment of colorectal cancer (review). Oncol Rep. 2003;10(5):1625-1631.
Singh B, Lucci A. Role of cyclooxygenase-2 in breast cancer. J Surg Res. 2002;108(1):173-179.
Srimuangwong K, Tocharus C, Tocharus J, Suksamrarn A, Chintana PY. Effects of hexahydrocurcumin in combination with 5-fluorouracil on dimethylhydrazine-induced colon cancer in rats. World J Gastroenterol. 2012;18(47):6951-6959.
Su CW, Zhang Y, Zhu YT. Stromal COX-2 signaling are correlated with colorectal cancer: A review. Crit Rev Oncol Hematol. 2016;107(33-38.
Sun Y, Tang XM, Half E, Kuo MT, Sinicrope FA. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res. 2002;62(21):6323-6328.
Takahashi M, Mutoh M, Kawamori T, Sugimura T, Wakabayashi K. Altered expression of beta-catenin, inducible nitric oxide synthase and cyclooxygenase-2 in azoxymethane-induced rat colon carcinogenesis. Carcinogenesis. 2000;21(7):1319-1327.
Tao L, Yang JK, Gu Y, Zhou X, Zhao AG, Zheng J, et al. Weichang’an and 5-fluorouracil suppresses colorectal cancer in a mouse model. World J Gastroenterol . 2015;21(4):1125-1139.
Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10(3):181-193.
Wang W, VanAlstyne PC, Irons KA, Chen S, Stewart JW, Birt DF. Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest in human colon carcinoma cell lines. Nutr Cancer. 2004;48(1):106-114.
Woo KJ, Jeong YJ, Park JW, Kwon TK. Chrysin-induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem Biophys Res Commun. 2004;325(4):1215-1222.
Zhang DQ, Guo Q, Zhu JH, Chen WC. Increase of cyclooxygenase-2 inhibition with celecoxib combined with 5-FU enhances tumor cell apoptosis and antitumor efficacy in a subcutaneous implantation tumor model of human colon cancer. World J Surg Oncol. 2013;11:16.
Zhang T, Chen X, Qu L, Wu J, Cui R, Zhao Y. Chrysin and its phosphate ester inhibit cell proliferation and induce apoptosis in Hela cells. Bioorg Med Chem . 2004;12(23):6097-6105.
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