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Direct renin inhibitor (DRI), aliskiren, is widely used as an anti-hypertensive agent in the clinical practice, and several reports have shown that renin plays an important role in several pathological processes. However, the role of renin in the hepatocarcinogenesis is still obscure. The aim of the current study was to examine the effect of DRI on the hepatocarcinogenesis in the rat model. Hepatocarcinogenesis model was induced in male F344 rats by the choline-deficient L-amino acid-defined diet for 12 weeks. The effect of DRI at clinically comparable low dose on the hepatocarcinogenesis was examined especially in conjunction with neovascularization. DRI exerted a marked inhibitory effect on the glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions along with suppression of the neovascularization in a dose-dependent manner. DRI also inhibited the hepatic expressions of angiotensin-II (AT-II), and vascular endothelial growth factor (VEGF). Our in vitro study showed that renin significantly augmented the in-vitro angiogenesis, whereas, interestingly, DRI did not inhibit the renin-induced the endothelial cell proliferation even at high dose. These results indicate that renin plays a pivotal role in hepatocarcinogenesis at least partly mediated by pro-angiogenic activity. Since DRI is already widely used in the clinical practice with safety, this drug may represent a potential new strategy against the hepatocarcinogenesis in the future. Citation Format: Yosuke Aihara, Hitoshi Yoshiji, Ryuichi Noguchi, Kosuke Kaji, Tadashi Namisaki, Kei Moriya, Mitsuteru Kitade, Hiroshi Fukui. Direct renin inhibitor attenuates rat hepatocarcinogenesis via anti-angiogenic activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5099. doi:10.1158/1538-7445.AM2013-5099

The incidence of hepatocellular carcinoma (HCC) is increasing not only in Asia but also in Europe and United States. Since the high-risk group of either primary or secondary HCC development seems to be clearer than in the other types of tumors, it is likely that chemopreventive agents will be beneficial in improving the prognosis of HCC. No chemopreventive agent, however, has been approved against HCC yet. Since neovascularization plays a pivotal role in HCC, an angiostatic agent is considered as one of the promising approaches. Although an anti-angiogenic agent, sorafenib has approved for advanced heparocellular carcinoma (HCC), most of patients show adverse effects in liver cirrhosis. Insulin resistance (IR) is reportedly involved in the progression of HCC partly mediated with neovascularization. The aim of this study was to develop the response-guided anti-angiogenic therapy with a clinically used safe agent; branched-chain amino acid (BCAA), which reportedly possess anti-angiogenic and IR improving activities, for the cumulative recurrence of HCC after curative therapy. BCAA (Livact; 12 g/day) was administered after the curative therapy for HCC, and 60-month follow-up revealed that the BCAA markedly inhibited the cumulative recurrence of HCC under the condition of IR along with suppression of VEGF. Chronological studies reveled that the VEGF and AFP-L3 were significantly decreased in patients without recurrence at 6 and 12 months after the treatment, respectively. The soluble VEGFR (sVEGFR)-2 was significantly suppressed only in patients without recurrence, whereas sVEGFR-1 was not. A marked suppression of sVEGFR-2 could be achieved within only three months after the treatment. Collectively, since BCAA is widely and safely used in the clinical practice to treat the patients with chronic liver diseases, BCAA may represent a new strategy for secondary chemoprevention for the HCC patients with IR. Moreover, our findings suggest that sVEGFR-2 could become a useful response-guided predictive marker of anti-angiogenic therapy against HCC by BCAA under the condition of IR. Citation Format: Hitoshi Yoshiji, Ryuichi Noguchi, Kosuke Kaji, Yosuke Aihara, Tadashi Namisaki, Kei Moriya, Akitoshi Douhara, Mitsuteru Kitade, Hiroshi Fukui. Response-guided anti-angiogenic therapy for hepatocellular carcinoma recurrence with clinically available safety agent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5078. doi:10.1158/1538-7445.AM2013-5078

A strong correlation between insulin resistance (IR) and hepatocellular carcinoma (HCC) has recently been identified, although little is known about the possible mechanisms involved. IR is a consistent finding in patients with type 2 diabetes mellitus (DM), and a close interaction between DM and HCC has been documented. Since neovascularization plays an important role in HCC including hepatocarcinogenesis, an angiostatic therapy would be a promising approach for chemoprevention against HCC. The aims of this study were to elucidate the role of angiogenesis in IR-based hepatocarcinogenesis, and to elucidate the therapeutic effect of combination of clinically used branched-chain amino acids (BCAA) and angiotensin-converting enzyme inhibitor (ACE-I), in conjunction with neovascularization. The combined effects on the development of liver enzyme-altered pre-neoplastic lesions, angiogenesis, and several indices were elucidated in obese diabetic rats. We also performed several sets of in-vitro experiments to examine the mechanisms involved. The IR status directly accelerated hepatocarcinogenesis, and treatment with both BCAA and ACE-I markedly inhibited the development of pre-neoplastic lesions under the condition of IR along with suppression of angiogenesis and VEGF expression in the liver. The combination treatment with BCAA and ACE-I exerted more potent inhibitory effects than single-agent treatments. Our in-vitro study demonstrated that BCAA and ACE-I inhibited the endothelial tubular formation almost in parallel with suppression of development of pre-neoplastic lesions. This combination regimen with BCAA and ACE-I showed a marked chemopreventive effect against hepatocarcinogenesis along with suppression of neovascularization and VEGF expression in obese diabetic rat as compared with either single-agent treatment. These inhibitory effects were achieved at clinically comparable low doses. Since both BCAA and ACE-I are widely used in the clinical practice, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2469.

Hepatocellular carcinoma (HCC) is now a major health problem. Since the high-risk group of either primary or secondary HCC development seems to be clearer than in the other types of tumors, it is likely that chemopreventive agents will be beneficial in improving the prognosis of HCC. In addition to assessment of tumor growth, recent studies have demonstrated that angiogenesis plays a pivotal role in the hepatocarcinogenesis process. Although several anti-angiogenic agents have already been employed in the clinical practice, most patients show adverse reactions with new drugs. An alternative approach may be to find a clinically available compound that also exhibits anti-angiogenic activity for which the safety of long-term administration has been proven. We previously reported that angiotensin-II (AT-II) was a prerequisite for hepatocarcinogenesis. Suppression of AT-II by angiotensin-converting enzyme inhibitor attenuates hepatocarcinogenesis via-suppression of neovascularization in the clinical practice. Recent studies have also suggested possible involvement of aldosterone (Ald) in neovascularization. The aim of our current study was to elucidate the effect of the clinically used eplerenone, a selective Ald blocker (SAB), on the rat hepatocarcinogenesis especially in conjunction with angiogenesis. We employed the rat hepatocarcinogenesis model, induced by feeding the rats on a choline-deficient, L-amino acid-defined diet without any carcinogen (CDAA model). The effects of SAB on the development of liver enzyme (namely, the placental form of glutathione-S-transferase (GST-P))-altered pre-neoplastic lesions and angiogenesis were examined. We also performed an in-vitro study to elucidate the possible mechanisms involved. Treatment with SAB markedly inhibited GST-P-positive lesions along with suppression of neovascularization. The hepatic vascular endothelial growth factor (VEGF) was also significantly attenuated. Our in-vitro study showed that Ald augmented both proliferation and tubule formation of the endothelial cells, and that SAB inhibited both activities in a dose-dependent manner via inhibition of phosphorylation of the extracellular signal-regulated kinase 1/2. These results indicated that, as well as AT-II, Ald plays a pivotal role in hepatocarcinogenesis, and that augmentation of angiogenesis is involved. Since SAB is already widely used in the clinical practice with proved safety, this drug may represent a potential new strategy for chemoprevention against HCC in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2470.

The incidence of hepatocellular carcinoma (HCC) is increasing not only in Asia but also in Europe and United States. Since the high-risk group of either primary or secondary HCC development seems to be clearer than in the other types of tumors, it is likely that chemopreventive agents will be beneficial in improving the prognosis of HCC. No chemopreventive agent, however, has been approved against HCC yet. Since neovascularization plays a pivotal role in HCC, an angiostatic agent is considered as one of the promising approaches. Although the multi-kinase inhibitor, sorafenib, has recently been approved for advanced HCC in many countries, there seem to be several serious concerns to employ this agent for chemoprevention against HCC. As long-term administration is required and the drug metabolism is usually hypoactive in patients with cirrhosis, a safety-proved agent would be preferable for chemoprevention against HCC. Most patients show adverse reactions with sorafenib, and several symptoms are very severe. The aim of this study was to develop a vascular endothelial growth factor (VEGF)-targeted new anti-angiogenic therapy against HCC using combination of clinically available safe agents. Moreover, since it is an imperative issue to find serum predictive biomarkers of clinical benefit, we tried to find a useful marker. We previously reported that the clinically used anti-osteoporosis agent; vitamin K (VK), and the anti-hypertensive agent; angiotensin-converting enzyme inhibitor (ACE-I), exerted potent anti-angiogenic activities along with suppression of VEGF at clinically comparable low doses in a basic study. In the clinical practice, the combination treatment of VK (menatetrenone; 45 mg/day) and ACE-I (perindopril; 4 mg/day) markedly inhibited the cumulative recurrence of HCC along with suppression of VEGF for 54 months after curative therapy. The serum level of alpha fetoprotein-L3 (AFP-L3), which indicates the presence of latent HCC, was also suppressed almost in parallel with VEGF. Chronological studies reveled that the VEGF and AFP-L3 were significantly decreased in patients without recurrence at 6 and 12 months after the treatment, respectively. We also examined the alteration of soluble form of VEGF receptor-2 (sVEGFR-2), and found that a significant suppression of sVEGFR-2 level could be achieved within three months after the treatment. Collectively, the alteration of the serum level of VEGF-related proteins, especially VEGFR-2, could be used as a biomarker for the therapeutic efficacy. These results indicate that this combination treatment may represent a potential new strategy for secondary chemoprevention of HCC with effective prediction of the clinical outcome since both agents are widely used in the clinical practice without serious side effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3439.

It is now widely recognized that angiogenesis is a crucial step in the development of tumors, including hepatocellular carcinoma (HCC). Therapies targeting the tumor vessels have proven successful for cancer treatment in experimental models and, in the clinical practice, several anti-angiogenic agents have already been employed. The renin-angiotensin-aldosterone system (RAAS) has also become known as a prerequisite for tumor angiogenesis, including HCC. We previously reported that angiotensin-II (AT-II) plays an important role in HCC development, and that suppression of AT-II by angiotensin-converting enzyme (ACE) inhibitor attenuated the tumor growth of HCC via suppression of intra-tumoral angiogenesis. Recent studies have also suggested the possible involvement of aldosterone (Ald) in neovascularization, although the actual role of Ald in tumor angiogenesis is still vague. The aim of our current study was to elucidate the effect of eplerenone (Epl), a clinically used selective Ald blocker, on HCC development, especially in conjunction with angiogenesis, using subcutaneous HCC model. To create an allograft model, we injected 1×106 of BNL-HCC cells into the flanks of BALB/c mice. The administration of Epl by daily gavage at a dose of 100 mg/kg/day was started on day 14, when the mean tumor volume was ∼ 200 mm3. The tumor volume was measured twice a week, and the mice were killed 35 days after tumor cell implantation. Administration of Epl at clinically comparable low dose could suppress HCC development as compared with the non-treated control. Epl treatment resulted in a marked increase of TUNEL-positive apoptosis in the tumor, whereas Ki67-positive tumor cell proliferation was not altered. Both CD31-immunopositive neo-vessels and VEGF expression in the tumor were markedly suppressed by this treatment in a magnitude similar to the inhibitory effect on the tumor growth. Our in-vitro study showed that Epl significantly suppressed the Ald-induced endothelial proliferation and tubular formation via inhibition of phosphorylation of the extracellular signal-regulated kinase 1/2. On the other hand, neither Ald nor Epl affected the proliferation of HCC cells. In conclusion, these results indicated that aldosterone plays a pivotal role in HCC development via VEGF-mediated tumor angiogenesis, and that Epl may be a potential new strategy for HCC therapy in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2468.