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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats

Authors: Norihisa Nishimura, Kosuke Kaji, Mitsuteru Kitade, Yosuke Aihara, Shinya Sato, Kenichiro Seki, Yasuhiko Sawada, Hiroaki Takaya, Yasushi Okura, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki, Akira Mitoro, Hitoshi Yoshiji

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes.

Methods

Male diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs).

Results

OLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment.

Conclusions

ACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.
Appendix
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Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRef
2.
Castells A, Bruix J, Bru C, Fuster J, Vilana R, Navasa M, et al. Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology. 1993;18(5):1121–6.PubMed
3.
Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25(2):181–200.CrossRef
4.
Siddique A, Kowdley KV. Insulin resistance and other metabolic risk factors in the pathogenesis of hepatocellular carcinoma. Clinics in liver disease. 2011;15(2):281–96 vii-x.CrossRef
5.
Loftfield E, Freedman ND, Lai GY, Weinstein SJ, McGlynn KA, Taylor PR, et al. Higher glucose and insulin levels are associated with risk of liver Cancer and chronic liver disease mortality among men without a history of diabetes. Cancer Prev Res. 2016;9(11):866–74.CrossRef
6.
Simon TG, King LY, Chong DQ, Nguyen LH, Ma Y, VoPham T, et al. Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies. Hepatology. 2018;67(5):1797-806.CrossRef
7.
El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126(2):460–8.CrossRef
8.
Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 2005;54(4):533–9.CrossRef
9.
Kaji K, Yoshiji H, Kitade M, Ikenaka Y, Noguchi R, Yoshii J, et al. Impact of insulin resistance on the progression of chronic liver diseases. Int J Mol Med. 2008;22(6):801–8.PubMed
10.
Tateishi R, Okanoue T, Fujiwara N, Okita K, Kiyosawa K, Omata M, et al. Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. J Gastroenterol. 2015;50(3):350–60.CrossRef
11.
Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62(6):1723–30.CrossRef
12.
Araki H, Shidoji Y, Yamada Y, Moriwaki H, Muto Y. Retinoid agonist activities of synthetic geranyl geranoic acid derivatives. Biochem Biophys Res Commun. 1995;209(1):66–72.CrossRef
13.
Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med. 1999;340(13):1046–7.CrossRef
14.
Okita K, Izumi N, Matsui O, Tanaka K, Kaneko S, Moriwaki H, et al. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol. 2015;50(2):191–202.CrossRef
15.
Kagawa M, Sano T, Ishibashi N, Hashimoto M, Okuno M, Moriwaki H, et al. An acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-alpha expression and cell proliferation. Carcinogenesis. 2004;25(6):979–85.CrossRef
16.
Shimizu M, Shirakami Y, Imai K, Takai K, Moriwaki H. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: targeting phosphorylated retinoid X receptor-alpha for prevention of liver carcinogenesis. J Carcinog. 2012;11:11.CrossRef
17.
Funaki M, Kitabayashi J, Shimakami T, Nagata N, Sakai Y, Takegoshi K, et al. Peretinoin, an acyclic retinoid, inhibits hepatocarcinogenesis by suppressing sphingosine kinase 1 expression in vitro and in vivo. Sci Rep. 2017;7(1):16978.CrossRef
18.
Shimizu M, Sakai H, Shirakami Y, Iwasa J, Yasuda Y, Kubota M, et al. Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BLKS/J- +(db)/+Lepr(db) mice. Cancer Prev Res. 2011;4(1):128–36.CrossRef
19.
Yoshiji H, Yoshii J, Ikenaka Y, Noguchi R, Tsujinoue H, Nakatani T, et al. Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats. J Hepatol. 2002;37(1):22–30.CrossRef
20.
Yoshiji H, Yoshii J, Ikenaka Y, Noguchi R, Yanase K, Tsujinoue H, et al. Suppression of the renin-angiotensin system attenuates vascular endothelial growth factor-mediated tumor development and angiogenesis in murine hepatocellular carcinoma cells. Int J Oncol. 2002;20(6):1227–31.PubMed
21.
Yang Y, Wei RB, Xing Y, Tang L, Zheng XY, Wang ZC, et al. A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients. Metab Clin Exp. 2013;62(12):1858–66.CrossRef
22.
Yoshiji H, Noguchi R, Kaji K, Ikenaka Y, Shirai Y, Namisaki T, et al. Attenuation of insulin-resistance-based hepatocarcinogenesis and angiogenesis by combined treatment with branched-chain amino acids and angiotensin-converting enzyme inhibitor in obese diabetic rats. J Gastroenterol. 2010;45(4):443–50.CrossRef
23.
Kato J, Koda M, Kishina M, Tokunaga S, Matono T, Sugihara T, et al. Therapeutic effects of angiotensin II type 1 receptor blocker, irbesartan, on non-alcoholic steatohepatitis using FLS-Ob/Ob male mice. Int J Mol Med. 2012;30(1):107–13.PubMed
24.
Suzui M, Masuda M, Lim JT, Albanese C, Pestell RG, Weinstein IB. Growth inhibition of human hepatoma cells by acyclic retinoid is associated with induction of p21(CIP1) and inhibition of expression of cyclin D1. Cancer Res. 2002;62(14):3997–4006.PubMed
25.
Peairs KS, Barone BB, Snyder CF, Yeh HC, Stein KB, Derr RL, et al. Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2011;29(1):40–6.CrossRef
26.
Colangelo LA, Gapstur SM, Gann PH, Dyer AR, Liu K. Colorectal cancer mortality and factors related to the insulin resistance syndrome. Cancer Epidemiol, Biomarkers Prev : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002;11(4):385–91.
27.
Carreras-Torres R, Johansson M, Gaborieau V, Haycock PC, Wade KH, Relton CL, et al. The role of obesity, type 2 diabetes, and metabolic factors in pancreatic Cancer: a Mendelian randomization study. J Natl Cancer Inst. 2017;109(9). https://​doi.​org/​10.​1093/​jnci/​djx012.
28.
Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int: official journal of the International Association for the Study of the Liver. 2015;35(10):2203–17.CrossRef
29.
Escudero CA, Herlitz K, Troncoso F, Guevara K, Acurio J, Aguayo C, et al. Pro-angiogenic role of insulin: from physiology to pathology. Front Physiol. 2017;8:204.CrossRef
30.
Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Shirai Y, et al. Possible involvement of angiogenesis in chronic liver diseases: interaction among renin-angiotensin-aldosterone system, insulin resistance and oxidative stress. Curr Med Chem. 2012;19(12):1889–98.CrossRef
31.
Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106(16):2067–72.CrossRef
32.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30.CrossRef
33.
Bertrand F, Philippe C, Antoine PJ, Baud L, Groyer A, Capeau J, et al. Insulin activates nuclear factor kappa B in mammalian cells through a Raf-1-mediated pathway. J Biol Chem. 1995;270(41):24435–41.CrossRef
34.
Manowsky J, Camargo RG, Kipp AP, Henkel J, Puschel GP. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes. Am J Physiol Endocrinol Metab. 2016;310(11):E938–46.CrossRef
35.
Matsushima-Nishiwaki R, Okuno M, Adachi S, Sano T, Akita K, Moriwaki H, et al. Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. Cancer Res. 2001;61(20):7675–82.PubMed
36.
Oura K, Tadokoro T, Fujihara S, Morishita A, Chiyo T, Samukawa E, et al. Telmisartan inhibits hepatocellular carcinoma cell proliferation in vitro by inducing cell cycle arrest. Oncol Rep. 2017;38(5):2825–35.CrossRef
37.
Amano Y, Yamaguchi T, Ohno K, Niimi T, Orita M, Sakashita H, et al. Structural basis for telmisartan-mediated partial activation of PPAR gamma. Hypertens Res: official journal of the Japanese Society of Hypertension. 2012;35(7):715–9.CrossRef
38.
Kerbel RS. Clinical trials of antiangiogenic drugs: opportunities, problems, and assessment of initial results. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2001;19(18 Suppl):45S–51S.
39.
Saif MW. Anti-angiogenesis therapy in pancreatic carcinoma. JOP : Journal of the pancreas. 2006;7(2):163–73.PubMed
40.
Scappaticci FA, Smith R, Pathak A, Schloss D, Lum B, Cao Y, et al. Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice. Mol Ther: the journal of the American Society of Gene Therapy. 2001;3(2):186–96.CrossRef
41.
Yoshiji H, Noguchi R, Toyohara M, Ikenaka Y, Kitade M, Kaji K, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol. 2009;51(2):315–21.CrossRef
42.
Escudero P, Navarro A, Ferrando C, Furio E, Gonzalez-Navarro H, Juez M, et al. Combined treatment with bexarotene and rosuvastatin reduces angiotensin-II-induced abdominal aortic aneurysm in apoE(−/−) mice and angiogenesis. Br J Pharmacol. 2015;172(12):2946–60.CrossRef
43.
Fu J, Wang W, Liu YH, Lu H, Luo Y. In vitro anti-angiogenic properties of LGD1069, a selective retinoid X-receptor agonist through down-regulating Runx2 expression on human endothelial cells. BMC Cancer. 2011;11:227.CrossRef
44.
Qin XY, Tatsukawa H, Hitomi K, Shirakami Y, Ishibashi N, Shimizu M, et al. Metabolome analyses uncovered a novel inhibitory effect of acyclic retinoid on aberrant lipogenesis in a mouse Diethylnitrosamine-induced hepatic tumorigenesis model. Cancer Prev Res. 2016;9(3):205–14.CrossRef
45.
Hirose A, Ono M, Saibara T, Nozaki Y, Masuda K, Yoshioka A, et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology. 2007;45(6):1375–81.CrossRef
46.
Montez P, Vazquez-Medina JP, Rodriguez R, Thorwald MA, Viscarra JA, Lam L, et al. Angiotensin receptor blockade recovers hepatic UCP2 expression and aconitase and SDH activities and ameliorates hepatic oxidative damage in insulin resistant rats. Endocrinology. 2012;153(12):5746–59.CrossRef
47.
Toffanin S, Friedman SL, Llovet JM. Obesity, inflammatory signaling, and hepatocellular carcinoma-an enlarging link. Cancer Cell. 2010;17(2):115–7.CrossRef
48.
Obora A, Shiratori Y, Okuno M, Adachi S, Takano Y, Matsushima-Nishiwaki R, et al. Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells. Hepatology. 2002;36(5):1115–24.CrossRef
49.
Tatebe H, Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Tsurumi H, et al. Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells. Cancer Lett. 2009;285(2):210–7.CrossRef
50.
Kanamori T, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Kojima S, et al. Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells. Cancer Sci. 2007;98(3):431–7.CrossRef
51.
Kubota M, Shimizu M, Baba A, Ohno T, Kochi T, Shirakami Y, et al. Combination of bevacizumab and acyclic retinoid inhibits the growth of hepatocellular carcinoma xenografts. J Nutr Sci Vitaminol. 2014;60(5):357–62.CrossRef
Metadata
Title
Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats
Authors
Norihisa Nishimura
Kosuke Kaji
Mitsuteru Kitade
Yosuke Aihara
Shinya Sato
Kenichiro Seki
Yasuhiko Sawada
Hiroaki Takaya
Yasushi Okura
Hideto Kawaratani
Kei Moriya
Tadashi Namisaki
Akira Mitoro
Hitoshi Yoshiji
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5099-6

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