Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats
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 experimen...
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| Format: | Article |
| Language: | English |
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BMC
2018-11-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-018-5099-6 |
| _version_ | 1818023342147371008 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Norihisa Nishimura |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T03:42:48Z |
| format | Article |
| id | doaj.art-16262ff9db40415792988b77c8bb8280 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-10T03:42:48Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-16262ff9db40415792988b77c8bb82802022-12-22T02:03:30ZengBMCBMC Cancer1471-24072018-11-0118111210.1186/s12885-018-5099-6Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF ratsNorihisa Nishimura0Kosuke Kaji1Mitsuteru Kitade2Yosuke Aihara3Shinya Sato4Kenichiro Seki5Yasuhiko Sawada6Hiroaki Takaya7Yasushi Okura8Hideto Kawaratani9Kei Moriya10Tadashi Namisaki11Akira Mitoro12Hitoshi Yoshiji13Third Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityThird Department of Internal Medicine, Nara Medical UniversityAbstract 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.http://link.springer.com/article/10.1186/s12885-018-5099-6Acyclic retinoidARBHepatocarcinogenesisChemopreventionInsulin resistance |
| spellingShingle | 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 Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats BMC Cancer Acyclic retinoid ARB Hepatocarcinogenesis Chemoprevention Insulin resistance |
| title | Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats |
| title_full | Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats |
| title_fullStr | Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats |
| title_full_unstemmed | Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats |
| title_short | Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats |
| title_sort | acyclic retinoid and angiotensin ii receptor blocker exert a combined protective effect against diethylnitrosamine induced hepatocarcinogenesis in diabetic oletf rats |
| topic | Acyclic retinoid ARB Hepatocarcinogenesis Chemoprevention Insulin resistance |
| url | http://link.springer.com/article/10.1186/s12885-018-5099-6 |
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