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

Abstract

BackgroundInsulin 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.MethodsMale 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).ResultsOLETF 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.ConclusionsACR 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5099-6) contains supplementary material, which is available to authorized users.

Peretinoin, an Acyclic Retinoid, for the Secondary Prevention of Hepatocellular Carcinoma

“…Therefore, the dose of peretinoin (2 × 600 mg/day) might be considered high as for the anticancer drug under clinical development. To exert more effective and satisfactory outcomes of ACR to enable HCC chemoprevention, the combination therapy of ACR with more potent anticancer agents would be considered [ 49 , 56 ].…”

Transition from normal to cancerous cell by precancerous niche (PCN) induced chronic cell-matrix stress

“…Losartan (Los) suppresses fibrosis in cardiac muscle in mice [227], as well as inflammation and beta amyloid in rats [228]. Los decreases aszites in ovarian cancer [229], and experimental hepatocarcinogenesis and HCC development together with acyclic retinoid (ACR) [230] as well as tumor progression from DCIS to invasive cancer in breast cancer cell lines [231]. The Los effect appears to be associated through the suppression of THBS1 [232][233][234] with consecutive decrease of TGF-b1, via decreases in the MAPK and NF-jB pathways in B and T cells [235] and induced antifibrotic miRNAs [229].…”