Resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

Zunino,Susan  J.; Storms,David  H.

doi:10.3892/ol.2017.6392

Resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

Authors:
- Susan J. Zunino
- David H. Storms
View Affiliations

Affiliations: Immunity and Disease Prevention Unit, United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616, USA
Published online on: June 16, 2017 https://doi.org/10.3892/ol.2017.6392
Pages: 2517-2522

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol‑4'‑O‑glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co‑treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end‑labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP‑ribose polymerase. It was identified that pretreatment of the cells with resveratrol‑3‑O‑glucuronide and resveratrol‑4'‑O‑glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with topoisomerase I inhibitors.

View Figures

View References

1	Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S and Takada Y: Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. Anticancer Res. 24:2783–2840. 2004.PubMed/NCBI
2	Brown VA, Patel KR, Viskaduraki M, Crowell JA, Perloff M, Booth TD, Vasilinin G, Sen A, Schinas AM, Piccirilli G, et al: Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: Safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 70:9003–9011. 2010. View Article : Google Scholar : PubMed/NCBI
3	Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP and Brown K: Clinical trials of resveratrol. Ann NY Acad Sci. 1215:161–169. 2011. View Article : Google Scholar : PubMed/NCBI
4	Walle T, Hsieh F, DeLegge MH, Oatis JE Jr and Walle UK: High absorption but very low bioavailability of oral resveratrol in humans. Drug Metabol Dispos. 32:1377–1382. 2004. View Article : Google Scholar
5	Vitrac X, Desmoulière A, Brouillaud B, Krisa S, Deffieux G, Barthe N, Rosenbaum J and Mérillon JM: Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sci. 72:2219–2233. 2003. View Article : Google Scholar : PubMed/NCBI
6	Wenzel E, Soldo T, Erbersdobler H and Somoza V: Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food Res. 49:482–494. 2005. View Article : Google Scholar : PubMed/NCBI
7	Crozier A, Jaganath IB and Clifford MN: Dietary phenolics: Chemistry, bioavailability and effects on health. Nat Prod Rep. 26:1001–1043. 2009. View Article : Google Scholar : PubMed/NCBI
8	van Duynhoven J, Vaughan EE, Jacobs DM, Kemperman RA, van Velzen EJ, Gross G, Roger LC, Possemiers S, Smilde AK, Doré J, et al: Metabolic fate of polyphenols in the human superorganism. Proc Natl Acad Sci USA. 108 Suppl 1:pp. 4531–4538. 2011; View Article : Google Scholar : PubMed/NCBI
9	Rotches-Ribalta M, Andres-Lacueva C, Estruch R, Escribano E and Urpi-Sarda M: Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacol Res. 66:375–382. 2012. View Article : Google Scholar : PubMed/NCBI
10	Radko Y, Christensen KB and Christensen LP: Semi-preparative isolation of dihydroresveratrol-3-O-β-d-glucuronide and four resveratrol conjugates from human urine after oral intake of a resveratrol-containing dietary supplement. J Chromatogr B Analyt Technol Biomed Life Sci. 930:54–61. 2013. View Article : Google Scholar : PubMed/NCBI
11	Bode LM, Bunzel D, Huch M, Cho GS, Ruhland D, Bunzel M, Bub A, Franz CM and Kulling SE: In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota. Am J Clin Nutr. 97:295–309. 2013. View Article : Google Scholar : PubMed/NCBI
12	Jung CM, Heinze TM, Schnackenberg LK, Mullis LB, Elkins SA, Elkins CA, Steele RS and Sutherland JB: Interaction of dietary resveratrol with animal-associated bacteria. FEMS Microbiol Lett. 297:266–273. 2009. View Article : Google Scholar : PubMed/NCBI
13	Azorín-Ortuño M, Yáñez-Gascón MJ, Vallejo F, Pallarés FJ, Larrosa M, Lucas R, Morales JC, Tomás-Barberán FA, García-Conesa MT and Espín JC: Metabolites and tissue distribution of resveratrol in the pig. Mol Nutr Food Res. 55:1154–1168. 2011. View Article : Google Scholar : PubMed/NCBI
14	Liu LF, Desai SD, Li TK, Mao Y, Sun M and Sim SP: Mechanism of action of campothecin. Ann N Y Acad Sci. 922:1–10. 2000. View Article : Google Scholar : PubMed/NCBI
15	Kuo LJ and Yang LX: Gamma-H2AX-a novel biomarker for DNA double-strand breaks. In Vivo. 22:305–309. 2008.PubMed/NCBI
16	Gavrieli Y, Sherman Y and Ben-Sasson SA: Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 119:493–501. 1992. View Article : Google Scholar : PubMed/NCBI
17	Rogakou EP, Pilch DR, Orr AH, Ivanova VS and Bonner WM: DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 273:5858–5868. 1998. View Article : Google Scholar : PubMed/NCBI
18	Shiloh Y: ATM and related protein kinases: Safeguarding genome integrity. Nat Rev Cancer. 3:155–168. 2003. View Article : Google Scholar : PubMed/NCBI
19	Fernandez-Capetillo O, Lee A, Nussenzweig M and Nussenzweig A: H2AX: The histone guardian of the genome. DNA Repair (Amst). 3:959–967. 2004. View Article : Google Scholar : PubMed/NCBI
20	Srivastava N, Gochhait S, de Boer P and Bamezai RN: Role of H2AX in DNA damage response and human cancers. Mutat Res. 682:180–188. 2009. View Article : Google Scholar
21	Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K and Bonner W: Histone H2A variants H2AX and H2AZ. Curr Opin Genet Dev. 12:162–169. 2002. View Article : Google Scholar : PubMed/NCBI
22	Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE and Lichten M: Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr Biol. 14:1703–1711. 2004. View Article : Google Scholar : PubMed/NCBI
23	Bom D, Curran DP, Kruszewski S, Zimmer SG, Strode J Thompson, Kohlhagen G, Du W, Chavan AJ, Fraley KA, Bingcang AL, et al: The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem. 43:3970–3980. 2000. View Article : Google Scholar : PubMed/NCBI
24	Van Hattum AH, Pinedo HM, Schlüper HM, Hausheer FH and Boven E: New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer. Int J Cancer. 88:260–266. 2000. View Article : Google Scholar : PubMed/NCBI
25	Colin D, Limagne E, Jeanningros S, Jacquel A, Lizard G, Athias A, Gambert P, Hichami A, Latruffe N, Solary E and Delmas D: Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells. Cancer Prev Res (Phila). 4:1095–1106. 2011. View Article : Google Scholar : PubMed/NCBI
26	Li G, He S, Chang L, Lu H, Zhang H, Zhang H and Chiu J: GADD45α and Annexin A1 are involved in the apoptosis of HL-60 induced by resveratrol. Phytomedicine. 18:704–709. 2011. View Article : Google Scholar : PubMed/NCBI
27	Kartal M, Saydam G, Sahin F and Baran Y: Resveratrol triggers apoptosis through ceramide metabolizing genes in human K562 chronic myeloid leukemia cells. Nutr Cancer. 63:637–644. 2011. View Article : Google Scholar : PubMed/NCBI
28	Gupta SC, Kannappan R, Reuter S, Kim JH and Aggarwal BB: Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci. 1215:150–160. 2011. View Article : Google Scholar : PubMed/NCBI
29	Banerjee S, Bueso-Ramos C and Aggarwal BB: Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: Role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloproteinase 9. Cancer Res. 62:4945–4954. 2002.PubMed/NCBI
30	Li ZG, Hong T, Shimada Y, Komoto I, Kawabe A, Ding Y, Kaganoi J, Hashimoto Y and Imamura M: Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. Carcinogenesis. 23:1531–1536. 2002. View Article : Google Scholar : PubMed/NCBI
31	Lee EO, Lee HJ, Hwang HS, Ahn KS, Chae C, Kang KS, Lu J and Kim SH: Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis. 27:2059–2069. 2006. View Article : Google Scholar : PubMed/NCBI
32	Liu HS, Pan CE, Yang W and Liu XM: Antitumor and immunomodulatory activity of resveratrol on experimentally implanted tumor of H22 in Balb/c mice. World J Gastroenterol. 9:1474–1476. 2003. View Article : Google Scholar : PubMed/NCBI
33	Tessitore L, Davit A, Sarotto I and Caderni G: Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis. 21:1619–1622. 2000. View Article : Google Scholar : PubMed/NCBI
34	Baur JA and Sinclair DA: Therapeutic potential of resveratrol: The in vivo evidence. Nat Rev Drug Discov. 5:493–506. 2006. View Article : Google Scholar : PubMed/NCBI
35	Kimura Y and Okuda H: Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in lewis lung carcinoma-bearing mice. J Nutr. 131:1844–1849. 2001.PubMed/NCBI
36	Busquets S, Ametller E, Fuster G, Olivan M, Raab V, Argilés JM and López-Soriano FJ: Resveratrol, a natural diphenol, reduces metastatic growth in an experimental cancer model. Cancer Lett. 245:144–148. 2007. View Article : Google Scholar : PubMed/NCBI
37	Weng YL, Liao HF, Li AF, Chang JC and Chiou RY: Oral administration of resveratrol in suppression of pulmonary metastasis of BALB/c mice challenged with CT26 colorectal adenocarcinoma cells. Mol Nutr Food Res. 54:259–267. 2010. View Article : Google Scholar : PubMed/NCBI
38	Cadenas S and Barja G: Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Free Radic Biol Med. 26:1531–1537. 1999. View Article : Google Scholar : PubMed/NCBI
39	Quincozes-Santos A, Andreazza AC, Nardin P, Funchal C, Gonçalves CA and Gottfried C: Resveratrol attenuates oxidative-induced DNA damage in C6 glioma cells. Neurotoxicology. 28:886–891. 2007. View Article : Google Scholar : PubMed/NCBI
40	Burkhardt S, Reiter RJ, Tan DX, Hardeland R, Cabrera J and Karbownik M: DNA oxidatively damaged by chromium(III) and H(2)O(2) is protected by the antioxidants melatonin, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, resveratrol and uric acid. Int J Biochem Cell Biol. 33:775–783. 2001. View Article : Google Scholar : PubMed/NCBI
41	Liu GA and Zheng RL: Protection against damaged DNA in the single cell by polyphenols. Pharmazie. 57:852–854. 2002.PubMed/NCBI
42	Russell GK, Gupta RC and Vadhanam MV: Effect of phytochemical intervention on dibenzo[a,l]pyrene-induced DNA adduct formation. Mutat Res. 774:25–32. 2015. View Article : Google Scholar : PubMed/NCBI
43	Singh K, Bhori M and Marar T: α-Tocopherol mediated amelioration of camptothecin-induced free radical damage to avert cardiotoxicities. Hum Exp Toxicol. 34:380–389. 2015. View Article : Google Scholar : PubMed/NCBI
44	Singh KC, Kaur R and Marar T: Ameliorative effect of vitamin E on chemotherapy induced side effects in rat liver. J Pharmacol Toxicol. 6:481–492. 2011. View Article : Google Scholar
45	Singh KC and Marar T: Acute toxicity of camptothecin and influence of α-tocopherol on hematological and biochemical parameters. J Cell Tiss Res. 11:2833–2837. 2011.
46	Guo Y, Shi M, Shen X, Yang C, Yang L and Zhang J: Capecitabine plus irinotecan versus 5-FU/leucovorin plus irinotecan in the treatment of colorectal cancer: A meta-analysis. Clin Colorectal Cancer. 13:110–118. 2014. View Article : Google Scholar : PubMed/NCBI
47	Vanhoefer U, Harstrick A, Achterrath W, Cao S, Seeber S and Rustum YM: Irinotecan in the treatment of colorectal cancer: Clinical overview. J Clin Oncol. 19:1501–1518. 2001. View Article : Google Scholar : PubMed/NCBI
48	Fujita K, Kubota Y, Ishida H and Sasaki Y: Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. World J Gastroenterol. 21:12234–12248. 2015. View Article : Google Scholar : PubMed/NCBI