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Open Access 01-08-2019 | Original Article—Alimentary Tract

Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma

Authors: Ayaka Mizumoto, Shinya Ohashi, Mayumi Kamada, Tomoki Saito, Yukie Nakai, Kiichiro Baba, Kenshiro Hirohashi, Yosuke Mitani, Osamu Kikuchi, Junichi Matsubara, Atsushi Yamada, Tsukasa Takahashi, Hyunjin Lee, Yasushi Okuno, Masashi Kanai, Manabu Muto

Published in: Journal of Gastroenterology | Issue 8/2019

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is one of the most intractable cancers, so the development of novel therapeutics has been required to improve patient outcomes. Curcumin, a polyphenol from Curcuma longa, exhibits various health benefits including antitumor effects, but its clinical utility is limited because of low bioavailability. Theracurmin^® (THC) is a highly bioavailable curcumin dispersed with colloidal submicron particles.

Methods

We examined antitumor effects of THC on ESCC cells by cell viability assay, colony and spheroid formation assay, and xenograft models. To reveal its mechanisms, we investigated the levels of reactive oxygen species (ROS) and performed microarray gene expression analysis. According to those analyses, we focused on NQO1, which involved in the removal of ROS, and examined the effects of NQO1-knockdown or overexpression on THC treatment. Moreover, the therapeutic effect of THC and NQO1 inhibitor on ESCC patient-derived xenografts (PDX) was investigated.

Results

THC caused cytotoxicity in ESCC cells, and suppressed the growth of xenografted tumors more efficiently than curcumin. THC increased ROS levels and activated the NRF2–NMRAL2P–NQO1 expressions. Inhibition of NQO1 in ESCC cells by shRNA or NQO1 inhibitor resulted in an increased sensitivity of cells to THC, whereas overexpression of NQO1 antagonized it. Notably, NQO1 inhibitor significantly enhanced the antitumor effects of THC in ESCC PDX tumors.

Conclusions

These findings suggest the potential usefulness of THC and its combination with NQO1 inhibitor as a therapeutic option for ESCC.

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Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–50.CrossRefPubMed

Ohashi S, Miyamoto S, Kikuchi O, et al. Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology. 2015;149:1700–15.CrossRefPubMed

Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRefPubMed

Smyth EC, Lagergren J, Fitzgerald RC, et al. Oesophageal cancer. Nat Rev Dis Primers. 2017;3:17048.CrossRefPubMedPubMedCentral

Pennathur A, Gibson MK, Jobe BA, et al. Oesophageal carcinoma. The Lancet. 2013;381:400–12.CrossRef

Tachimori Y, Ozawa S, Numasaki H, et al. Comprehensive registry of esophageal cancer in Japan, 2009. Esophagus. 2016;13:110–37.CrossRefPubMedPubMedCentral

Goel A, Jhurani S, Aggarwal BB. Multi-targeted therapy by curcumin: how spicy is it? Mol Nutr Food Res. 2008;52:1010–30.CrossRefPubMed

Kanai M. Therapeutic applications of curcumin for patients with pancreatic cancer. World J Gastroenterol. 2014;20:9384–91.PubMedPubMedCentral

Prasad S, Gupta SC, Tyagi AK, et al. Curcumin, a component of golden spice: from bedside to bench and back. Biotechnol Adv. 2014;32:1053–64.CrossRefPubMed

10.

Lev-Ari S, Starr A, Katzburg S, et al. Curcumin induces apoptosis and inhibits growth of orthotopic human non-small cell lung cancer xenografts. J Nutr Biochem. 2014;25:843–50.CrossRefPubMed

11.

Perry MC, Demeule M, Regina A, et al. Curcumin inhibits tumor growth and angiogenesis in glioblastoma xenografts. Mol Nutr Food Res. 2010;54:1192–201.PubMed

12.

Lim TG, Lee SY, Huang Z, et al. Curcumin suppresses proliferation of colon cancer cells by targeting CDK2. Cancer Prev Res (Phila). 2014;7:466–74.CrossRef

13.

Ma J, Fang B, Zeng F, et al. Curcumin inhibits cell growth and invasion through up-regulation of miR-7 in pancreatic cancer cells. Toxicol Lett. 2014;231:82–91.CrossRefPubMed

14.

Guo H, Xu YM, Ye ZQ, et al. Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor. Pharmazie. 2013;68:431–4.PubMed

15.

Ye F, Zhang GH, Guan BX, et al. Suppression of esophageal cancer cell growth using curcumin, (−)-epigallocatechin-3-gallate and lovastatin. World J Gastroenterol. 2012;18:126–35.CrossRefPubMedPubMedCentral

16.

Tian F, Fan T, Zhang Y, et al. Curcumin potentiates the antitumor effects of 5-FU in treatment of esophageal squamous carcinoma cells through downregulating the activation of NF-kappaB signaling pathway in vitro and in vivo. Acta Biochim Biophys Sin (Shanghai). 2012;44:847–55.CrossRef

17.

Tian F, Zhang C, Tian W, et al. Comparison of the effect of p65 siRNA and curcumin in promoting apoptosis in esophageal squamous cell carcinoma cells and in nude mice. Oncol Rep. 2012;28:232–40.CrossRefPubMed

18.

Anand P, Kunnumakkara AB, Newman RA, et al. Bioavailability of curcumin: problems and promises. Mol Pharmaceutics. 2007;4:807–18.CrossRef

19.

Tonnesen HH, Masson M, Loftsson T. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int J Pharmaceutics. 2002;244:127–35.CrossRef

20.

Sharma RA, McLelland HR, Hill KA, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001;7:1894–900.PubMed

21.

Yang KY, Lin LC, Tseng TY, et al. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;853:183–9.CrossRefPubMed

22.

Sasaki H, Sunagawa Y, Takahashi K, et al. Innovative preparation of curcumin for improved oral bioavailability. Biol Pharmaceut Bull. 2011;34:660–5.CrossRef

23.

Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer. 2005;104:1322–31.CrossRefPubMed

24.

Liu A, Lou H, Zhao L, et al. Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin. J Pharm Biomed Anal. 2006;40:720–7.CrossRefPubMed

25.

Bisht S, Feldmann G, Soni S, et al. Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. J Nanobiotechnol. 2007;5:3.CrossRef

26.

Koppolu B, Rahimi M, Nattama S, et al. Development of multiple-layer polymeric particles for targeted and controlled drug delivery. Nanomedicine. 2010;6:355–61.CrossRefPubMed

27.

Yallapu MM, Ebeling MC, Khan S, et al. Novel curcumin-loaded magnetic nanoparticles for pancreatic cancer treatment. Mol Cancer Ther. 2013;12:1471–80.CrossRefPubMedPubMedCentral

28.

Nakagawa Y, Mukai S, Yamada S, et al. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci. 2014;19:933–9.CrossRefPubMedPubMedCentral

29.

Tanabe Y, Maeda S, Akazawa N, et al. Attenuation of indirect markers of eccentric exercise-induced muscle damage by curcumin. Eur J Appl Physiol. 2015;115:1949–57.CrossRefPubMedPubMedCentral

30.

Funamoto M, Sunagawa Y, Katanasaka Y, et al. Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:2029–34.CrossRefPubMedPubMedCentral

31.

Yamauchi Y, Izumi Y, Yamamoto J, et al. Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res. 2014;28:728–35.CrossRefPubMed

32.

Kang M, Ho JN, Kook HR, et al. Theracurmin(R) efficiently inhibits the growth of human prostate and bladder cancer cells via induction of apoptotic cell death and cell cycle arrest. Oncol Rep. 2016;35:1463–72.CrossRefPubMed

33.

Ross D, Siegel D. Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Front Physiol. 2017;8:595.CrossRefPubMedPubMedCentral

34.

Toda Y, Kono K, Abiru H, et al. Application of tyramide signal amplification system to immunohistochemistry: a potent method to localize antigens that are not detectable by ordinary method. Pathol Int. 1999;49:479–83.CrossRefPubMed

35.

Nishihira T, Hashimoto Y, Katayama M, et al. Molecular and cellular features of esophageal cancer cells. J Cancer Res Clin Oncol. 1993;119:441–9.CrossRefPubMed

36.

DeNicola GM, Chen PH, Mullarky E, et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet. 2015;47:1475–81.CrossRefPubMedPubMedCentral

37.

Yi YW, Oh S. Comparative analysis of NRF2-responsive gene expression in AcPC-1 pancreatic cancer cell line. Genes Genomics. 2015;37:97–109.CrossRefPubMed

38.

Johnson GS, Li J, Beaver LM, et al. A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells. Mol Nutr Food Res. 2017;61:1600749.

39.

Mitsuishi Y, Motohashi H, Yamamoto M. The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol. 2012;2:200.CrossRefPubMedPubMedCentral

40.

Zhang J, Jiao Q, Kong L, et al. Nrf2 and Keap1 abnormalities in esophageal squamous cell carcinoma and association with the effect of chemoradiotherapy. Thorac Cancer. 2018;9:726–35.CrossRefPubMedPubMedCentral

41.

Winski SL, Faig M, Bianchet MA, et al. Characterization of a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1 by biochemical, X-ray crystallographic, and mass spectrometric approaches. Biochemistry. 2001;40:15135–42.CrossRefPubMed

42.

Zhou H, Dehn D, Kepa JK, et al. NAD(P)H:quinone oxidoreductase 1-compromised human bone marrow endothelial cells exhibit decreased adhesion molecule expression and CD34 + hematopoietic cell adhesion. J Pharmacol Exp Ther. 2010;334:260–8.CrossRefPubMedPubMedCentral

43.

Kanai M, Otsuka Y, Otsuka K, et al. A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients. Cancer Chemother Pharmacol. 2013;71:1521–30.CrossRefPubMed

44.

Wu B, Zhang XJ, Li XG, et al. Long non-coding RNA Loc344887 is a potential prognostic biomarker in non-small cell lung cancer. Eur Rev Med Pharmacol Sci. 2017;21:3808–12.PubMed

45.

Wu XC, Wang SH, Ou HH, et al. The NmrA-like family domain containing 1 pseudogene Loc344887 is amplified in gallbladder cancer and promotes epithelial-mesenchymal transition. Chem Biol Drug Des. 2017;90:456–63.CrossRefPubMed

46.

Bhaumik S, Anjum R, Rangaraj N, et al. Curcumin mediated apoptosis in AK-5 tumor cells involves the production of reactive oxygen intermediates. FEBS Lett. 1999;456:311–4.CrossRefPubMed

47.

Kim MS, Kang HJ, Moon A. Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. Arch Pharmacol Res. 2001;24:349–54.CrossRef

48.

Woo JH, Kim YH, Choi YJ, et al. Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis. 2003;24:1199–208.CrossRefPubMed

49.

Cao J, Jia L, Zhou HM, et al. Mitochondrial and nuclear DNA damage induced by curcumin in human hepatoma G2 cells. Toxicol Sci. 2006;91:476–83.CrossRefPubMed

50.

Xiao M, Yang H, Xu W, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326–38.CrossRefPubMedPubMedCentral

51.

Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.CrossRefPubMedPubMedCentral

52.

Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483:474–8.CrossRefPubMedPubMedCentral

53.

Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67.CrossRefPubMedPubMedCentral

54.

Siegel D, Bolton EM, Burr JA, et al. The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant. Mol Pharmacol. 1997;52:300–5.CrossRefPubMed

55.

Siegel D, Gustafson DL, Dehn DL, et al. NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol. 2004;65:1238–47.CrossRefPubMed

56.

Zhu H, Jia Z, Mahaney JE, et al. The highly expressed and inducible endogenous NAD(P)H:quinone oxidoreductase 1 in cardiovascular cells acts as a potential superoxide scavenger. Cardiovasc Toxicol. 2007;7:202–11.CrossRefPubMed

Title: Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma
Authors: Ayaka Mizumoto
Shinya Ohashi
Mayumi Kamada
Tomoki Saito
Yukie Nakai
Kiichiro Baba
Kenshiro Hirohashi
Yosuke Mitani
Osamu Kikuchi
Junichi Matsubara
Atsushi Yamada
Tsukasa Takahashi
Hyunjin Lee
Yasushi Okuno
Masashi Kanai
Manabu Muto
Publication date: 01-08-2019
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 8/2019
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-019-01549-x

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Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma

Abstract

Background

Methods

Results

Conclusions

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Abstract

Background

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Results

Conclusions

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