Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents

Yoshiji, Hitoshi; Noguchi, Ryuichi; Ikenaka, Yasuhide; Kaji, Kosuke; Shirai, Yusaku; Aihara, Yosuke; Yamao, Junichi; Toyohara, Masahisa; Mitoro, Akira; Sawai, Masayoshi; Yoshida, Motoyuki; Morioka, Chie; Fujimoto, Masao; Uemura, Mamoru; Kawaratani, Hideto; Tsujimoto, Tatsuhiro; Fukui, Hiroshi

doi:10.3892/ol.2010.196

Cited by 6 publications

(6 citation statements)

References 27 publications

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“…Table 1 reports the characteristics of all clinical studies selected. We found only three interventional studies, all performed by the same authors, which examined the influence of a putative antitumoral treatment after randomization of the patients[13-15]. These studies evaluated the influence of ACE-Is, given alone or in combination with either vitamin K or branched chain aminoacids (BCAA), on HCC recurrence, showing a significant protective effect of ACE-I only when used in combination with vitamin K or BCAA.…”

Section: Resultsmentioning

confidence: 99%

“…We had to wait about 10 years for the first clinical study on the possible role of ACE-Is administration in the recurrence of HCC[13]. This study, designed as a randomized trial, was followed within a couple of years by two similar randomized trials from the same authors, all demonstrating the efficacy of the ACE-I perindopril in reducing tumor recurrence when used in combination with other drugs[13-15]. Interestingly, this effect was associated with a significant reduction of VEGF[13-15] and alpha-fetoprotein[13,14] serum levels.…”

Section: Discussionmentioning

confidence: 99%

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Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

Barone¹,

Viggiani²,

Losurdo³

et al. 2019

WJG

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BACKGROUND Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs. AIM To elucidate the role of ARBs and ACE-Is in HCC. METHODS We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro . Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals. RESULTS Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. CONCLUSION In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

Barone¹,

Viggiani²,

Losurdo³

et al. 2019

WJG

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“…[ 13 ] In a small, prospective, randomized, open‐label trial, patients with HCC were randomized either to ACEIs plus vitamin K or no treatment; the cumulative HCC recurrence rate was lower in the ACEI‐treated patients than in untreated patients (~40% vs. 75% recurrence [ p < 0.01]). [ 14 ]…”

Section: Figurementioning

confidence: 99%

ACE inhibitors: The secret to prevent cirrhosis complications and HCC in NAFLD?

Noureddin

Abdelmalek²

2022

Hepatology

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The secret to prevent cirrhosis complications and HCC in NAFLD?NAFLD, and its progressive form NASH, is currently the leading cause of chronic liver disease worldwide, accounting for an alarming increase in prevalence of cirrhosis, HCC, hepatic decompensation, and need for liver transplantation. [1] Risk factors for acquisition and progression of NAFLD/NASH include features of metabolic syndrome such as diabetes mellitus, cardiovascular disease, and hypertension. The Eight Joint National Committee advises on the use of use of angiotensinconverting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as first-line drugs for the management of hypertension and lend to cardiovascular protection in vulnerable populations. [2] In a recent retrospective cohort study of 12,327 adult patients with NAFLD, Zhang et al. [3] reported that ACEI treatment was associated with a lower risk of liver-related events (weighted subdistribution HR [sHR], 0.48; 95% CI, 0.35-0.66; p < 0.001), HCC (weighted sHR, 0.46; 95% CI, 0.28-0.75; p = 0.002), and cirrhosis complications (weighted sHR, 0.42; 95% CI, 0.27-0.66; p < 0.001). Such reduction in liver-related events was also notable with patients without chronic kidney disease (CKD) than in those without CKD (CKD-weighted sHR, 0.74; 95% CI, 0.52-0.96; p = 0.036; non-CKD-weighted SHR, 0.15; 95% CI, 0.07-0.33; p < 0.001). [3] These very compelling results beg the question as to whether use of ACEI, a usual treatment for hypertension and cardiovascular disease, should broadly be used as a repurposed drug for the treatment of NAFLD/NASH.ACEIs and ARBs, collectively called renin-angiotensin system inhibitors, inhibit vasoconstriction and sodium retention, leading to blood pressure control. Inhibition of the renin-angiotensin aldosterone system (RAAS) has been demonstrated to reduce fibrogenesis in various organs, including the liver. The local RAAS has been implicated in multiple functions including cell growth, differentiation, proliferation and apoptosis, reactive oxygen species generation, tissue inflammation, fibrogenesis, and hormonal secretion. [4] Several studies in a variety of established animal models of hepatic fibrosis support the role of RAAS in liver fibrosis and the antifibrotic effects of RAAS inhibition. Treatment with ACEIs and ARBs in

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“…61 Several interventional studies examined the effects of ACE inhibitors alone or in combination with other drugs in patients after RFA; these showed that ACE inhibitors reduced the risk of HCC recurrence in combination with branched-chain amino acids (BCAAs) or vitamin K, but no significant OS benefit was observed. [62][63][64] Thus, although the results for patient survival with RAS inhibitors appear to be contradictory, this accumulating evidence suggests that RAS inhibitors may work to reduce the occurrence of HCC. There are some remarkable studies on whether the use of β-blockers benefits patients after HCC treatment or puts them at a high risk of carcinogenesis.…”

Section: Prevention Of Hcc Occurrence With Antihypertensive Drugsmentioning

confidence: 99%

“… Yoshiji et al 62 (2009) RCT Patients after curative treatment for HCC ACE-I / vitamin K suppressed VEGF-mediated neovascularization. Yoshiji et al 63 (2011) RCT Patients after curative treatment for HCC ACE-I / vitamin K suppressed VEGF-mediated neovascularization. Yoshiji et al 64 (2011) RCT Patients after curative treatment for HCC ACE-I / BCAA effected anti-angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma

Oura¹,

Morishita²,

Tani³

et al. 2022

JHC

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Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.

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Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents

Cited by 6 publications

References 27 publications

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

ACE inhibitors: The secret to prevent cirrhosis complications and HCC in NAFLD?

Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma

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