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Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as therapeutic options in the treatment of renal cancer: A meta-analysis
Abstract
Aims:
Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) which have been used in the treatment of cardiovascular diseases, have also been shown to have anti-tumor effects against various cancers that include renal cancer. The aim of current paper was to explore the potential clinical impact of ACEI/ARB inhibitors in renal cancer.
Main methods:
We used several databases: EMBASE, PubMed and the Cochrane library, to identify clinical studies that assessed the relationship between ACEIs/ARBs treatment and risk of renal cancer incidence or survival of renal cancer patients. The hazard ratio (HR) with 95% confidence intervals were obtained for assessing the relationship between ACEIs/ARBs and renal cancer mortality.
Key finding:
The HR for the relationship between ASIs use and survival of renal cancer indicated that patients with renal cancer being treated with ACEIs/ARBs had a significantly lower mortality than non-user (HR 0.723, 95% CI 0.568-0.921, p = 0.009). The HR for the relationship between ACEIs use and survival of renal cancer indicated that patients with renal cancer that used ACEIs had a higher mortality than non-users (HR 1.352, 95% CI 0.917-1.991, p = 0.128). The HR for the relationship between ARBs use and survival of renal cancer indicated that patients with renal cancer that used ARBs had a decreased of mortality than non-users (HR 0.818, 95% CI 0.691-0.969, p = 0.02).
Significance:
This meta-analysis demonstrated that treatment with ACEIs/ARBs may improve renal cancer survival and reduce the mortality of patients with renal cancer.
... There is growing evidence suggesting a possible association between cancer incidence and the use of angiotensin II receptor type 1 (ATR1) blockers, that are used in the management of hypertension and cardiovascular disease. ATR1 have been shown to be upregulated in various cancer cells including melanoma, glioblastoma, prostate, renal, bladder, breast, and pancreatic cancer (Miyajima et al., 2002;Du et al., 2012;Renziehausen, 2017;Renziehausen et al., 2019;Afsar et al., 2021;Arjmand et al., 2020;Asgharzadeh et al., 2020a). The overexpression of ATR1 was reported to be associated with the malignant features of tumors by inducing angiotensin II. ...
... AT1R blockers, such as candesartan, losartan, and valsartan are commonly used as anti-hypertensive drugs in patients with cardiovascular diseases (Minatoguchi et al., 2013;Abraham et al., 2015). There is growing evidence that suggests that the suppression of angiotensin II receptor signaling by AT1R blockers can inhibit tumor progression in several types of cancers including renal, colon, breast, bladder, and prostate cancer (Piastowska-Ciesielska et al., 2013;Arrieta et al., 2015;Asgharzadeh et al., 2018Asgharzadeh et al., , 2020aHashemzehi et al., 2021a, b). Candesartan has been reported to inhibit cancer cell growth and development in multiple human tumors when used alone or in combination with other anticancer drugs (Molteni et al., 2006;Fan et al., 2016;Ishikane and Takahashi-Yanaga, 2018). ...
... The therapeutic potential of inhibiting the renin-angiotensin system using AT1R blockers appears to be promising for the management of various cancers including breast, bladder, pancreas, prostate, renal, and colon cancer (Kosugi et al., 2009;Chen et al., 2013;Alhusban et al., 2014;Okazaki et al., 2014;Asgharzadeh et al., 2018Asgharzadeh et al., , 2020a. In this study, we used systems and molecular biology to explore the molecular mechanisms of the anti-tumor effects of candesartan in CRC progression in cellular and animal models. ...
Colorectal cancer (CRC) is an important cause of cancer-related mortality. Aberrant activation of the renin-angiotensin system (RAS) is reported to be associated with poor clinical outcomes in patients with CRC. This study was designed to explore the anti-tumor effects of the angiotensin receptor blocker Candesartan either alone or in combination with 5-FU in in vitro and in vivo models of CRC. The cytotoxic effects of Candesartan were assessed using the MTT assay in two colorectal cancer cell lines (CT-26 and SW-480). To investigate the potential regulatory role of Candesartan on tumor growth, apoptosis, and migration, the expression levels of Cyclin D1, Survivin, MMP3, MMP9, and E-cadherin mRNAs were evaluated. The oxidant/antioxidant balance was also examined by determining the levels of MDA, thiols, SOD, and CAT. We used a xenograft model of colon cancer to investigate the effects of Candesartan alone, or in combination with 5-FU, on tumor growth following histological staining (Hematoxylin & Eosin and Masson trichrome staining) and biochemical studies as well as gene expression analyses by RT-PCR and western blotting. Candesartan suppressed tumor cell proliferation and migration by modulating Cyclin D1, MMP3/9, and E-cadherin. Treatment with Candesartan either alone, or in combination with 5-FU decreased tumor size in the mouse model, and also increased the level of oxidative markers MDA and reduced CAT, SOD, and thiols. Histological evaluation showed that Candesartan increased tumor necrosis, reduced tumor density and attenuated collagen deposition reducing tumor fibrosis in tumor xenograft. Candesartan, an inhibitor of the RAS, when used in combination with 5-FU reduced tumor growth by inhibiting fibrosis and inducing ROS production, supporting further clinical studies on this therapeutic approach for treatment of CRC.
... Studies involving pharmacotherapeutic agents suggest that inhibition of protein synthesis, which has been activated as a result of reactive oxygen species, is one way that targeted therapy could be achieved, as elaborated by Vassalle et al. [232]. Most drugs with antioxidant properties, such as those used in the treatment of CVD, have simultaneous effects in relation to oxidative stress, i.e., beta blocks, angiotensin-converting enzymes (ACE), and angiotensin receptor blockers (ARB) have multiple effects on different pathways [233]. Therapeutic agents such as statins show both antioxidant and anti-inflammatory properties, as there is a reduction in cytokine production once administered [234]. ...
... Therapeutic agents such as statins show both antioxidant and anti-inflammatory properties, as there is a reduction in cytokine production once administered [234]. Recent studies have shown that statins improve both blood vessel and heart-related diseases and achieve this by inhibiting specific proteins such as Rac and Rho [233,235]. The pharmacological effect of statins is through targeting and blocking a coenzyme known as hydroxylmethylgrutaryl A reductase. ...
Metabolic syndrome is a cluster of conditions associated with the risk of diabetes mellitus type 2 and cardiovascular diseases (CVDs). Metabolic syndrome is closely related to obesity. Increased adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving metabolic syndrome components, namely insulin resistance, hypertension, and hyperlipidemia. An increasing number of studies confirm the importance of oxidative stress and chronic inflammation in the etiology of metabolic syndrome. However, few studies have reviewed the mechanisms underlying the role of oxidative stress in contributing to metabolic syndrome. In this review, we highlight mechanisms by which reactive oxygen species (ROS) increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant function in metabolic syndrome. Biomarkers of oxidative stress can be used in disease diagnosis and evaluation of severity.
... There are some significant zinc-dependent metalloenzymes like matrix metalloproteinases (MMPs), TNF-α converting enzyme (TACE), carbonic anhydrases (CAs), angiotensin-converting enzyme (ACE), carboxypeptidase A, thermolysin, etc. These metalloproteinases are responsible for executing various biological functions [3][4][5][6][7]. Therefore, these enzymes are an excellent target as they are engaged in a variety of human ailments namely cardiovascular and neurodegenerative disorders, rheumatoid arthritis, and cancer [2]. ...
... We did not retrieve any association between use of ACEis and one-year mortality in this specific population. These observations were consistent with other studies as the effects of ACEis in cancer risk and survival are still debated [25,35]. In 2018, Hicks et al. found that long-term use of ACEis was specifically associated to an increased risk of lung cancer compared to ARBs in a population base cohort study of 992,061 patients newly treated with antihypertensive drugs [36]. ...
Simple Summary
The involvement of the renin-angiotensin pathway in both the regulation of the cardiovascular system and in tumorigenesis raises the question of the prognostic impact of renin-angiotensin system blockers (RABs) in cancer patients experiencing life-threatening complications. The aim of our retrospective study was to assess this impact in solid tumor patients requiring unplanned ICU admission over a 14-year period. Among 1845 patients mainly diagnosed with gastrointestinal and lung cancers, 414 (22.4%) were treated with RABs: 220 (53.1%) with angiotensin-receptor blockers (ARBs) and 194 (46.9%) with angiotensin-converting enzyme inhibitors (ACEis). ARBs use and ACEis use were both associated with improved in-ICU survival, whereas only ARBs use was associated with improved one-year survival.
Abstract
Increasing evidence argues for the promotion of tumorigenesis through activation of the renin-angiotensin system pathway. Accordingly, a benefit of renin-angiotensin system blockers (RABs) treatments has been suggested in patients with solid cancers in terms of survival. We aimed to evaluate in-ICU survival and one-year survival in cancer patients admitted to the ICU with respect to the use of RABs. We conducted a retrospective observational single-center study in a 24-bed medical ICU. We included all solid cancer patients (age ≥ 18 years) requiring unplanned ICU admission. From 2007 to 2020, 1845 patients with solid malignancies were admitted (median age 67 years (59–75), males 61.7%). The most frequent primary tumor sites were the gastrointestinal tract (26.8%), the lung (24.7%), the urological tract (20.1%), and gynecologic and breast cancers (13.9%). RABs were used in 414 patients, distributed into 220 (53.1%) with angiotensin-receptor blockers (ARBs) and 194 (46.9%) with angiotensin-converting enzyme inhibitors (ACEis). After multivariate adjustment, ARBs use (OR = 0.62, 95%CI (0.40–0.92), p = 0.03) and ACEis use (OR = 0.52, 95%CI (0.32–0.82), p = 0.006) were both associated with improved in-ICU survival. Treatment with ARBs was independently associated with decreased one-year mortality (OR = 0.6, 95%CI (0.4–0.9), p = 0.02), whereas treatment with ACEis was not. In conclusion, this study argues for a beneficial impact of RABs use on the prognosis of critically ill cancer patients.
... Sun et al. [4] conducted a meta-analysis and found a nonsignificant trend toward better metastasis-free survival among RAS inhibitor users (hazard ratio [HR] = 0.63; 95% confidence interval [CI] = 0.40-1.01). Conversely, Asgharzadeh et al. [5] conducted a meta-analysis of the association between use of RAS inhibitors and survival rates among patients with kidney cancer and revealed significantly higher mortality rates in patients treated with RAS inhibitors than in those who did not receive RAS inhibitors (HR = 0.723, 95% CI = 0.568-0.921). These reports suggest that RAS inhibitors may reduce cancer metastasis, which leads to better prognosis. ...
... On this note, a meta-analysis specifically on renal cancer demonstrated that ACEIs/ARBs use improves renal cancer survival and reduces the mortality of these patients [24]. Regarding digestive system malignancies, a meta-analysis of 13 studies showed ACEIs/ARBs to improve overall survival and recurrence-free survival [25]. ...
Background
: In this study we investigated the therapeutic potential of angiotensin II pathway inhibitors in attenuating post-surgical adhesion band formation in tendon injury.
Method
: We assigned 30 Wistar albino rats to 5 groups, including negative control, positive control, sham, Telmisartan- and Enalapril-treated groups (n=6). Telmisartan and Enalapril at a dose of 10 mg/kg were administered intraperitoneally for 21 days. Hematoxylin-Eosin, and Masson's trichrome staining were used to measure the inflammatory cell accumulation and collagen deposition in the Achilles tendon tissue sections. Oxidative stress markers were analyzed in tissue samples by spectrophotometric methods. Properties of Achilles tendon adhesions were compared based on Tang and Ishiyama scoring systems in the presence and absence of angiotensin II pathway inhibitors.
Results
: Telmisartan and Enalapril reduced severity, length, and density of surgical-induced tendon adhesion at site of injury (***p < 0.001). Our results showed that administration of angiotensin II pathway inhibitors decreased infiltration of inflammatory cells to the injured area (*p < 0.05) and suppressed inflammation by regulating oxidative stress markers including MDA (***p < 0.001), total thiol (***p < 0.001), CAT (***p < 0.001), and SOD (***p < 0.001), in post-operative Achilles tendon tissues. Significant lower collagen deposition and formation of fibrotic tissues was seen in Telmisartan- and Enalapril-treated groups as detected by Masson's trichrome staining which correlated with a decrease in quantity (**p < 0.01) and grading of fibrosis score (***p < 0.001), in adhesive tissues. Moreover, inhibition of angiotensin II pathway could also ameliorate mechanical properties including ultimate load (***p < 0.001), and ultimate stress (*p < 0.05) in injured Tendons.
Conclusion
: Our results showed that ssuppression of inflammation and fibrosis are two mechanisms by which Telmisartan and Enalapril elicit potent protective responses post Achilles tendon injuries.
... Several types of cancer cells and tissues have been shown to overexpress RAS components, including brain, lung, breast, prostate, skin and cervical carcinomas, as well as gastrointestinal malignancies and normal tissues (e.g. stomach, pancreas and colon) [9]. ...
Angiotensin receptor blockers (ARB), as well as angiotensin-converting enzyme inhibitors (ACEI), are mostly used as therapy for hypertension and cardiovascular disease. However, they can increase the risk of cancer progression including gastric cancer. Here we aimed to analyze the assessment between ARB and ACEI on the progression of gastric cancer. Cochrane Library, PubMed and EMBASE were searched for articles and abstracts describing ARBs, ACEIs, and incidence of gastric cancer. Risk ratio, hazard ratio and 95% confidence interval (CI) were extracted from each outcome by using a random-effects model. Six studies met our inclusion criteria. These results demonstrated that there is a significant association between ARB with gastric cancer progression (risk ratio = 0.63; 95% CI, 0.5-0.7; P = 0.00; I2 = 27.299; df (Q) = 2; Q-value = 2.75). However, there was not any link between ACEIs and gastric cancer development (risk ratio = 1.1; 95% CI, 0.92-1.31; P = 0.26; I2 = 0.00; df (Q) = 3; Q-value = 1.26). All these findings indicated that using the ARBs has raised the progression of gastric cancer in these patients.
... On this note, a meta-analysis specifically on renal cancer demonstrated that ACEIs/ARBs use improves renal cancer survival and reduces the mortality of these patients [24]. Regarding digestive system malignancies, a meta-analysis of 13 studies showed ACEIs/ARBs to improve overall survival and recurrence-free survival [25]. ...
The renin–angiotensin system (RAS) has been reported to have a role in carcinogenesis, and therefore it may be of value as a potential therapeutic target in inhibiting tumor growth. It has been shown that inhibition of RAS via angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor (ARBs) inhibitors may have a protective effect against several malignancies. Here we provide an overview on the potential value of RAS pathway and targeting via ACE/ARB inhibitors in pancreatic cancer. Whilst the potential role of RAS as a target for the treatment of pancreatic cancer has been reported, the use of candesartan with gemcitabine failed to improve outcomes in pancreatic cancer. Another study of 1–3 years using ARB was found to reduce the risk of pancreatic cancer. In line with these trials, there have been others demonstrating that the ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are warranted to investigate this hypothesis.
... Angiotensin-converting enzyme (AGCE) converts angiotensin I to angiotensin II, which is a growth factor responsible for angiogenesis in various types of cells including hepatic cancer cells. 53,54 An in vivo study deciphers that combination treatment of vitamin K2 and AGCE inhibitors, that is, perindopril and benazepril diethyl-nitrosamine, exhibited anticancer effect against HCC by inhibition of neovascularization and significant induction of apoptosis. [54][55][56] In a cohort study, the administration of the same combination therapy for 36-48 months has exhibited suppression of HCC recurrence and progression by significant inhibition of vascular endothelial growth factor (VEGF) and lectin-reactive α-fetoprotein serum level. ...
Cancer incidences are growing rapidly and causing millions of deaths globally.
... Angiotensin-converting enzyme (AGCE) converts angiotensin I to angiotensin II, which is a growth factor responsible for angiogenesis in various types of cells including hepatic cancer cells. 53,54 An in vivo study deciphers that combination treatment of vitamin K2 and AGCE inhibitors, that is, perindopril and benazepril diethyl-nitrosamine, exhibited anticancer effect against HCC by inhibition of neovascularization and significant induction of apoptosis. [54][55][56] In a cohort study, the administration of the same combination therapy for 36-48 months has exhibited suppression of HCC recurrence and progression by significant inhibition of vascular endothelial growth factor (VEGF) and lectin-reactive α-fetoprotein serum level. ...
Cancer incidences are growing rapidly and causing millions of deaths globally. Cancer treatment is one of the most exigent challenges. Drug resistance is a natural phenomenon and is considered as one of the major obstacles in successful treatment of cancer by chemotherapy. Combination therapy by amalgamation of various anticancer drugs has suggested modulating tumor response by targeting various signaling pathways in synergistic or additive manner. Vitamin K is an essential nutrient and have recently been investigated as a potential anticancer agent. Combination of Vitamin K analogues such as Vitamin K1, Vitamin K2, Vitamin K3 and Vitamin K5 with other chemotherapeutic drugs have demonstrated a safe, cost effective and most efficient way to overcome drug resistance and improve the outcomes of prevailing chemotherapy. Published research reports have shown that Vitamin K in combination therapy improved the efficacy of clinical drugs by promoting apoptosis and cell cycle arrest and overcome drug resistance by inhibiting P-glycoprotein. In
this review article, we discuss the mechanism, cellular targets and possible way to develop Vitamin K subtypes into effective cancer chemosensitizers. Finally, this review article will provide scientific basis for exploiting Vitamin K as a potential agent to improve the efficacy of chemotherapeutic drugs.
Keywords: Vitamin K, Combination therapy, Multiple signaling pathways, Cell cycle arrest, Apoptosis. Cancer chemosensitizers.
... Consistent with these findings, ARBs and ACEIs have been reported to reduce tumor growth and vascularization in a wide range of cancers, suggesting a role for Ang II in cancer development and progression [4]. We summarized the studies containing ARBs in the last ten years and revealed the effects on OS and DSS across different malignancies (Table 7) [5][6][7][8][18][19][20][21][22][23]. However, there was no consistent conclusion on whether ARBs have a survival benefit in patients coexisting with malignancies. ...
Objectives
Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with various cancers. However, it remains unclear whether ARBs confer a survival benefit on patients with oral squamous cell carcinoma (OSCC). Here, we assessed the associations between ARB use and survival in patients with OSCC of different stages.
Materials and methods
This was a 10-year retrospective cohort study of OSCC patients. We enrolled 7,558 patients diagnosed with oral cancer between January 2007 and December 2017 whose details had been entered into the Chang Gung Research Database. Seven hundred and fourteen patients were recruited from the Chang Gung Research Database after performing 1:1 propensity score-matching between ARB users and non-users. Cox’s regression models with adjusted covariates were employed to detect factors influencing the survival rates of patients with OSCC.
Results
Kaplan-Meier analysis revealed that the overall survival (OS) rate of 180-day ARB users increased ( p = 0.038). Cox’s regression models indicated that ARB use, younger patients, early-stage OSCC, and patients without diabetes mellitus were independently prognostic of improved OS. Increased OS was more prominent in 180-day ARB users in stage III, Iva, and IVb categories.
Conclusions
ARB use for more than 180 days is associated with an increased survival rate and is a positive, independent prognostic factor in patients with OSCC. A further two-arm study should be conducted to confirm the clinical usefulness of ARBs in OSCC patients.
... In a large nationwide Finnish cohort, the authors found a significant reduction in mortality due to breast cancer in RASB users, also featuring a doseeffect, suggesting a mechanistic association [84]. Similarly, concurring elements supported that urological cancer survival improved with RASB use [85][86][87][88][89]. In non-small-cell lung cancer, RASB use with platinum and taxol chemotherapy was associated with improved survival [90,91]. ...
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.
... Prevented LV fibrosis and remodeling after MI [94] There is also clinical evidence regarding the use of RAAS inhibitors in a variety of cancer types. Song et al. reported that the use of ACEIs reduced the risk of cancer recurrence and mortality by 40% and 25% when ARB was administered, showing significant effects for colorectal, urinary, pancreatic, and prostate cancer, but not in hepatocellular and breast cancer [95], and a positive association has also been noted for renal [96,97] and intestinal cancer [97]. However, the lack of association of the effect of these inhibitors on some types of cancer has also been reported [95], which could reflect the complex biology of cancer, including the specific characteristics of each tumor, since it has been described that tumors at different sites have their own intrinsic and extrinsic mechanisms, as well as concerning the presence of cardiovascular risk factors. ...
The current global prevalence of heart failure is estimated at 64.34 million cases, and it is expected to increase in the coming years, especially in countries with a medium-low sociodemographic index where the prevalence of risk factors is increasing alarmingly. Heart failure is associated with many comorbidities and among them, cancer has stood out as a contributor of death in these patients. This connection points out new challenges both in the context of the pathophysiological mechanisms involved, as well as in the quality of life of affected individuals. A hallmark of heart failure is chronic activation of the renin-angiotensin-aldosterone system, especially marked by a systemic increase in levels of angiotensin-II, a peptide with pleiotropic activities. Drugs that target the renin-angiotensin-aldosterone system have shown promising results both in the prevention of secondary cardiovascular events in myocardial infarction and heart failure, including a lower risk of certain cancers in these patients, as well as in current cancer therapies; therefore, understanding the mechanisms involved in this complex relationship will provide tools for a better diagnosis and treatment and to improve the prognosis and quality of life of people suffering from these two deadly diseases.
... This effect was closely related to the blockade of the energy uptake pathway in tumor cells, which resulted in a decrease in the number of proliferating cells [27]. Another meta-analysis showed that the survival rate improved for patients with renal cancer who received treatment with RASi compared to those who did not [28]. ...
The renin-angiotensin system (RAS) regulates physiological functions of the cardiovascular system, kidneys, and other tissues. Various in vivo and in vitro studies have shown that RAS plays a pivotal role in the development of malignant tumors, while several retrospective studies have confirmed that patients undergoing long-term RAS inhibitors (RASi) treatment have a lowered risk of cancer. Moreover, blocking RAS has been shown to inhibit tumor growth, metastasis, and angiogenesis in various experimental models of malignant tumors. Herein, we review the available RASi-related literature and provide an analysis using the scientific atlas software VOSviewer. We observed that recent studies have primarily focused on gene expression, tumor biology, and survival analysis. Through an in-depth data analysis from the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx), we identified the impact of AGTR1, an essential component of RAS, on tumors, and we discuss the underlying biological mechanism of RASi. Furthermore, we outline the research progress and potential use of RASi in tumor treatment. Overall, RASi may be a promising adjunct in cancer therapy.
... When RAS inhibitors are used in certain site-specific cancer, for example in breast cancer, there was no evidence to support better disease-free survival and overall survival (Raimondi et al., 2016). However, it can improve survival and reduce mortality in kidney cancer (Asgharzadeh et al., 2020a), and show beneficial outcomes in gastrointestinal cancer (Zhou et al., 2020). In response to partial incoherence, a systematic review and meta-analysis by Shen et al. (Shen et al., 2016) observed significant benefits of RAS inhibitors in case-control and cohort studies, whereas they were attenuated in randomized controlled trials. ...
Hypertension is the prevailing independent risk factor for cardiovascular disease worldwide. Anti-hypertensive drugs are the common and effective cure for lowering blood pressure in patients with hypertension. However, some large-scale clinical studies have pointed out that long-term ingestion of some oral anti-hypertensive drugs was associated with risks of incident cancer and the survival time. In contrast, other studies argue that anti-hypertensive drugs are not related to the occurrence of cancer, even as a complementary therapy of tumor treatment. To resolve the dispute, numerous recent mechanistic studies using animal models have tried to find the causal link between cancer and different anti-hypertensive drugs. However, the results were often contradictory. Such uncertainties have taken a toll on hypertensive patients. In this review, we will summarize advances of longitudinal studies in the association between anti-hypertensive drugs and related tumor risks that have helped to move the field forward from associative to causative conclusions, in hope of providing a reference for more rigorous and evidence-based clinical research on the topic to guide the clinical decision making.
... The same agents retain a role in cancer and neurodegenerative conditions suggesting that targeting common (in this case OxS-related) pathways may represent a successful pharmacological strategy for the prevention of multiple diseases, although always keeping in mind that the OxS damage does not represent the only event in the pathogenesis of these conditions [1,47]. ...
Oxidative stress (OxS) is one of the main processes related to aging and a common denominator of many different chronic/degenerative diseases (e.g., cardiovascular and neurodegenerative conditions and cancer). Thus, its potential modulation by supplementation/pharmacological therapy caused a lot of interest. However, these expectations have been mitigated by the obtainment of controversial results (beneficial, null, or adverse effects) following antioxidant interventions. Here, we discuss the current understanding of OxS assessment in health and disease, challenges and the potential of its evaluation in clinical practice, and available and future development for supplementation and pharmacologic strategies targeting OxS.
Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.
Olmesartan, originally known for its antihypertensive properties, exhibits promising potential in addressing inflammation-mediated diseases. As an angiotensin II receptor blocker (ARB), Olmesartan influences pivotal pathways, including reactive oxygen species, cytokines, NF-κB, TNF-α, and MAPK. This suggests a viable opportunity for repurposing the drug in conditions such as ulcerative colitis, neuropathy, nephropathy, and cancer, as supported by multiple preclinical studies. Ongoing clinical trials, particularly in cardiomyopathy and nephropathy, suggest a broader therapeutic scope for Olmesartan. Repurposing efforts would entail comprehensive investigations using disease-specific preclinical models and dedicated clinical studies. The drug’s established safety profile, wide availability, and well-understood ARB mechanism of action offer distinct advantages that could facilitate a streamlined repurposing process. In summary, Olmesartan’s versatile impact on inflammation-related pathways positions it as a promising candidate for repurposing across various diseases. Ongoing clinical trials and the drug’s favorable attributes enhance its appeal for further exploration and potential application in diverse medical contexts.
Background:
Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are mainly known as anti-hypertensive drugs. Recent evidence suggests their anti-tumor potential against renal cancer. More than one-fourth of patients present with metastasis on their first visit.
Objective:
The purpose of the current study was to examine the potential clinical impact of ACEI/ARB on metastatic renal cell carcinoma (mRCC).
Methods:
We searched through several online databases, including Pubmed, Scopus, Web of Science, and Embase, to find clinical studies that have investigated the association between treatment with ACEI/ARB and the survival of patients with mRCC. The hazard ratio (HR) and 95% confidence interval (95% CI) were utilized to assess the strength of the association.
Results:
A total of 6 studies with a total number of 2,364 patients were found eligible for the final analysis. The HR for the relationship between ACEI/ARB use and overall survival (OS) showed patients undergoing treatment with ACEI/ARB to have higher OS than non-users (HR: 0.664, 95% CI 0.577-0.764, p=0.000). Furthermore, the HR for the relationship between ACEI/ARB use and progression-free survival (PFS) showed patients undergoing treatment with ACEI/ARB to have higher PFS than non-users (HR: 0.734, 95% CI 0.695-0.794, p=0.000).
Conclusion:
The results of this review offer ACEI/ARB as a potential therapeutic option associated with improved survival outcomes in patients receiving anti-vascular endothelial growth factor therapy.
Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide angiotensin-(1-7). ACE2 and its product, angiotensin-(1-7), have counteracting effects against the adverse actions of other members of renin-angiotensin system (RAS). ACE2 and its principal product, angiotensin-(1-7), were considered an under recognized arm of the RAS. The COVID-19 pandemic brought to light this arm of RAS with special focus on ACE2. Membrane bound ACE2 serves as a receptor for SARS-CoV-2 viral entry through spike proteins. Apart from that, ACE2 is also involved in the pathogenesis of various other diseases like cardiovascular disease, cancer, respiratory diseases, neurodegenerative diseases and infertility. The present review focuses on the molecular mechanism of ACE2 in neurodegenerative diseases, cancer, cardiovascular disease, infertility and respiratory diseases, including SARS-CoV-2. This review summarizes unveiled roles of ACE2 in the pathogenesis of various diseases which further provides intriguing possibilities for the use of ACE2 activators and RAS modulating agents for various diseases.
This study investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cells (CSCs) we have recently demonstrated in renal clear cell carcinoma (RCCC). Fifteen RCCC tissue samples underwent immunohistochemical staining for components of the RAS: renin, pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin II receptor 2 (AT2R). Immunofluorescence co-staining or double immunohistochemical staining of these components of the RAS with stemness-associated markers OCT4 or KLF4 was performed on two of the samples. Protein and transcript expression of these components of the RAS in six RCCC tissue samples was investigated using western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, angiotensin II receptor 1 (AT1R) was investigated using RT-qPCR only. Immunohistochemical staining demonstrated expression of renin, PRR, and ACE2 in 11, 13, and 13 out of 15 RCCC samples, respectively, while AT2R was expressed in all 15 samples. ACE was detected in the endothelium of normal vasculature only. Double immunohistochemical staining demonstrated localization of ACE2, but not renin, to the KLF4+ CSCs. Immunofluorescence staining showed localization of PRR and AT2R to the OCT4+ CSCs. Western blotting confirmed protein expression of all components of the RAS except renin. RT-qPCR demonstrated transcript expression of all components of the RAS including AT1R, but not AT2R, in all six RCCC tissue samples. This study demonstrated expression of PRR, ACE2, and AT2R by the CSCs within RCCC. Further studies may lead to novel therapeutic targeting of CSCs by manipulation of the RAS in the treatment of this aggressive cancer.
Renal fibrosis is a common characteristic of chronic kidney disease (CKD), and it can lead to end-stage renal disease. It has been reported that silibinin or lisinopril (MK-521) can inhibit the progression of renal fibrosis. However, the effect of combination of silibinin with MK-521 on renal fibrosis remains unclear. Therefore, this study aimed to explore the combination of silibinin with MK-521 on renal fibrosis in vitro and in vivo. The cell viability of HK-2 was detected by CCK-8. The gene and protein expression in HK-2 cells were detected by qRT-PCR and Western blot, respectively. Moreover, HFD-induced renal fibrosis mouse model was established to investigate the effect of silibinin in combination with MK-521 on renal fibrosis in vivo. The expressions of collagen I, α-SMA, Smad2 and Smad3 in TGF-β-treated HK-2 cells were notably decreased by MK-521, which was further inhibited in the presence of silibinin. In addition, we found that silibinin significantly enhanced anti-fibrotic effect of MK-521 on HFD-induced renal fibrosis mice. These findings demonstrated that silibinin could significantly increase anti-fibrotic effect of MK-521 in vitro and in vivo. Therefore, the combination of silibinin with MK-521 may serve as a potential strategy for the treatment of renal fibrosis.
Kidney cancer represents about 5% of all new cancer diagnoses. The most common form of kidney cancer arises from renal epithelium, named renal cell carcinoma (RCC). This entity comprises different histological and molecular subtypes. Unraveling the molecular biology and cytogenetic of RCC has enabled the development of several targeted agents that have improved treatment outcomes of these patients. This article reviews all the agents currently approved for the treatment of RCC, and discuss upcoming molecules. Mechanism of action, preclinical and clinical development and ongoing trials, are presented for each agent, providing a broad vision of the current state of targeted therapy in RCC and possible future developments.
To examine the association between hypertension (HTN), Angiotensin System Inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).
We retrospectively reviewed all patients with mRCC who received SU as first line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre-existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HR) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, IMDC risk group and histology.
Among 213 patients with a 3.6 years median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the 2 exposures (p<0.0001). Hypertensive patients have longer OS (median: 41.6 vs 16.4 months, p<0.0001) and longer PFS (median: 12.9 vs 5.6 months, p<0.0001) than non-hypertensive patients (n=79). ASI users (n=105) had more HTN_PRE compared to those (n=108) who did not (65 vs 19%, p<0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (p=0.05) and marginally with PFS (p=0.06) while ASI intake was significantly associated with better OS (HR=0.40; 95% CI [0.24; 0.66], p<0.001) and PFS (HR=0.55 [0.35; 0.86], p=0.009). The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment.
Concomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients.
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
The two major classes of drugs that target the RAS are the angiotensin-converting enzyme (ACE) inhibitors and the selective AT1 receptor blockers (ARBs). Although both of these drug classes target angiotensin II, the differences in their mechanisms of action have implications for their effects on other pathways and receptors that may have therapeutic implications. Both ACEIs and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and renal events. Direct inhibition of renin -the most proximal aspect of the RAS -became clinically feasible from 2007 with the introduction of aliskiren. This latter drug has been shown to be efficacious for the management of hypertension. Combined therapy of direct renin-inhibitors with ACEIs or ARBs has been tested in some clinical situations as congestive HF and proteinuria with diverse results. This article tries to offer an updated review of current knowledge on the use of RAS blocking drugs in clinical settings.
The effect of captopril on tumour growth was examined in a xenograft model of human renal cell carcinoma (RCC). Inoculation of the human RCC cell line SN12K-1 (10(6) cells) under the left kidney capsule of severe combined immunodeficient (SCID) mice resulted in the growth of large tumours, with an increase in weight of the inoculated kidney of 3.69+/-1.63-fold (mean+/-s.d.) when compared with the contralateral normal kidney. In mice treated with captopril (19 mg kg(-1) day(-1) or 94 mg kg(-1) day(-1) administered in the drinking water), there was a significant dose-related reduction in tumour development; the tumour bearing kidneys weighed 1.9+/-0.42 and 1.55+/-0.42 times the normal kidneys, respectively (P< 0.05 compared with untreated animals). In vitro, captopril at clinically achievable doses (0.1-10 microM) had no significant effect on the incorporation of [3H]thymidine into SN12K-1 cells. Thus, this highly significant attenuation by captopril of in vivo tumour growth does not appear to be due to a direct effect on the proliferation of the tumour cells. Further studies are required to determine the mechanism of inhibition of tumour growth by captopril, in particular to evaluate the role of angiotensin II in this process.
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Several lines of evidence suggest that hypertension and angiogenesis may be related phenomena but a functional link remains elusive. Here, we propose that the renin-angiotensin system (RAS), in addition to its central role in arterial hypertension, also regulates blood vessel formation during normal development and cancer. This mechanistic hypothesis is based on reports of biochemical, genetic, clinical, and epidemiologic data reviewed herein. Species differences between the RAS of rodents and humans likely account for why such a fundamental role in angiogenesis went unrecognized for so long. If proven correct, this hypothesis carries many implications for the medical practices of cardiology, oncology, and neonatology.
Aim: Renal cell carcinoma (RCC) is the most frequent cancer among renal neoplasms in adults and poorly responsive to radio-, chemo- and immunotherapy. There is increasing evidence that blockade of RAS has antineoplasic effects. Objective: Investigate the effects of RAS blockade on renal cell carcinoma (RCC) in a murine model.
Methods: Murine renal cancer cells (RENCA) were cultivated and injected (1x10⁵) into subcapsular space of the left kidney of BALB/c mice (8 weeks). The animals were divided into 4 groups : control group (no treatment), Losartan (100 mg / kg / day), Captopril group (10 mg / kg / day) and Losartan + Captopril group (100 mg / kg / day + 10 mg / kg / day). The animals received the drugs by gavage 2 days before tumor induction and continued until euthanasia (21 days after inoculation). After sacrifice, kidneys and lungs were removed, weighed and processed for histopathological analysis. Angiogenesis and vascular microvessel were determined by immunohistochemical evaluation for VEGF and CD34.
Results: All inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension in relation to controls. The expressions of VEGF and CD34 were significantly decreased in renal tumors of animals treated compared with controls.
Conclusions: Our findings suggest that blockade of RAS decreases the tumor proliferation capacity and metastatic potential of renal cell carcinoma in this experimental model.
Disclosure: All authors have declared no conflicts of interest.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017. © 2017 American Cancer Society.
The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO “blue book”), published in 2016, contains significant revisions. These revisions were performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome–associated RCC, succinate dehydrogenase–deficient RCC, tubulocystic RCC, acquired cystic disease–associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non–GCNIS-related tumours in the 2016 WHO classification.
Patient summary
The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours.
Purpose: The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASIs) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. Methods: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. Results: 4,736 patients were included, of whom 1,487 received ASIs and 783 received other anti-hypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared to users of other anti-hypertensive agents (adjusted HR 0.838, p=0.0105, 26.68 versus 18.07 months) and individuals receiving no anti-hypertensive therapy (adjusted HR 0.810, p=0.0026, 26.68 versus 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared to non-users in individuals receiving vascular endothelial growth factor targeted therapy (adjusted HR 0.737, p<0.0001, 31.12 versus 21.94 months) but not temsirolimus or interferon-alpha. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared to control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI anti-hypertensives or temsirolimus. Conclusions: In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice.
Copyright © 2015, American Association for Cancer Research.
Angiotensin II type 1 receptor (AT1R) promotes tumor invasion, migration, metastasis and angiogenesis. We explored the potential antitumor effects of AT1R antagonists in breast cancer. We found that Angiotensin II promoted cell proliferation and upregulated the expression of vascular endothelial growth factor A (VEGF-A) in MCF-7 cells. Losartan downregulated the expression of VEGF-A in MCF-7 cells treated with angiotensin II. Candesartan downregulated the expression of VEGF-A in mice bearing MCF-7 xenografts and inhibited tumor growth and angiogenesis. AT1R and VEGF-A expression correlated with increased microvascular density in 102 breast cancer patients. Our data suggest that AT1R antagonists might be useful to suppress breast cancer by inhibiting the angiotensin II.
To investigate the association between angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) and disease progression and survival in cancer patients.
Using terms for cancer and ACEIs/ARBs, MEDLINE, EMBASE and Web of Science were systematically searched for observational/interventional studies that used clinically relevant outcomes for cancer progression and survival.
Ten studies met the inclusion criteria. Two studies showed a significant improvement in overall survival (OS) with ACEI/ARB use among patients with advanced pancreatic (HR 0.52, 95% CI 0.29-0.88) and non-small cell lung cancer (HR 0.56, 95% CI 0.33-0.95). An improvement in progression-free survival (PFS) was also reported for pancreatic cancer patients (HR 0.58, 95% CI 0.34-0.95) and patients with renal cell carcinoma (HR 0.54, p = 0.02). ACEI/ARB use was protective against breast cancer recurrence (HR 0.60, 95% CI 0.37-0.96), colorectal cancer distant metastasis (OR 0.22, 95% CI 0.08-0.65) and prostate specific antigen (PSA) failure in prostate cancer patients (p = 0.034). One study observed a worse OS (HR 2.01, 95% CI 1.00-4.05) and PFS in ACEI users with multiple myeloma (p = 0.085) while another reported an increased risk of breast cancer recurrence (HR = 1.56, 95% CI 1.02-2.39).
There is some evidence to suggest that ACEI or ARB use may be associated with improved outcomes in cancer patients. Larger, more robust studies are required to explore this relationship further.
Sunitinib is a standard treatment for metastatic renal cell carcinoma. Angiotensin system inhibitors, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, are widely used in hypertension, kidney disease and heart failure. Data suggests that they may inhibit tumourigenesis.
To study the effect of angiotensin system inhibitors on sunitinib treatment outcome in metastatic renal cell carcinoma.
We performed a retrospective study of an unselected cohort of patients with metastatic renal cell carcinoma who were treated with sunitinib. Patients were divided into angiotensin system inhibitors users (group 1) and non-users (group 2). The effect of angiotensin system inhibitors on objective response, time to disease progression and overall survival, was tested with adjustment for known confounding risk factors through logistic regression model and Cox regression model.
Between 2004 and 2010, 127 patients with metastatic renal cell carcinoma were treated with sunitinib, 44 group 1 and 83 group 2. The groups were balanced regarding known clinicopathologic prognostic factors. Objective response was partial response/stable disease 86% versus 72% and progressive disease 14% versus 28% (p=0.07) in group 1 versus 2, respectively. Median progression free survival was 13 versus 6 months (HR 0.537, p=0.0055), and median overall survival 30 versus 23 months (HR 0.688, p=0.21), in favour of group 1.
Angiotensin system inhibitors may improve the outcome of sunitinib treatment in metastatic renal cell carcinoma. This should be investigated prospectively, and if validated applied in clinical practise and clinical trials.
Previous studies have reported an increased risk of cancer with calcium-channel blockers in man. Other work in animals suggests that inhibitors of angiotensin-I-converting enzyme (ACE) protect against cancer. We aimed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs.
Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. The patients' records are linked with the Registrar General Scotland and the West of Scotland Cancer Registry.
Compared with the West of Scotland controls, the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0.72 (95% CI 0.55-0.92) and 0.65 (0.44-0.93). Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors (calcium-channel blockers 1416, diuretics 2099, beta-blockers 2681), the corresponding relative risks were 110 (0.97-1.22) and 1.03 (0.87-1.20). The relative risk of cancer was lowest in women on ACE inhibitors: 0.63 (0.41-0.93) for incident cancer; 0.48 (0.23-0.88) for fatal cancer; and 0.37 (0.12-0.87) for female-specific cancers. The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years. Calcium-channel blockers, diuretics, and beta-blockers had no apparent effect on risk of cancer.
Long-term use of ACE inhibitors may protect against cancer. The status of this finding is more that of hypothesis generation than of hypothesis testing; randomised controlled trials are needed.
The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power.
To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alpha to other options.
A search of MEDLINE, Cancerlit, EMBASE and Cochrane Library databases from 1966 through the end of 1999. Handsearches were made of the proceedings of the annual meetings of the American Urologic Association, ASCO, and biennial European ECCO meetings, and the references of identified studies.
Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported response or survival by allocation. Forty-two studies involving 4216 patients were eligible and reported response and 26 of these reported survival outcome (3089 patients).
Two independent reviewers abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment response (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alpha versus controls.
The average response rate was 10.2 % (range by arm, 0 - 39%) and complete response rate was 3.2% (123/3852; n = 38 studies). Median survival averaged 11.6 months (range by arm, 6 - 28 months) and two-year survival averaged 22% (16 studies, range by arm 8 - 41%). There were no placebo-controlled studies and no randomized controlled studies examined survival for high dose interleukin-2 versus controls. Results from 6 studies (n = 963) indicate that interferon-alpha is superior to controls (OR for death at one year = 0.67, 95% CI 0.50 - 0.89. The pooled hazard ratio for survival of 0.78 (0.67 - 0.90) indicates that the treatment effect persisted until 24 months from randomization. The weighted average median improvement in survival was 2.6 months. Additional comparisons failed to prove a survival benefit from the addition of other agents to either modified schedules of interleukin-2 or to interferon-alpha. Dose-response studies examining survival for either agent could not be identified. The difference in response rate between arms was correlated with the difference in survival (P<0.001) suggesting that response rate difference may be a surrogate intermediate endpoint for survival.
Interferon-alpha provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. Interleukin-2 has not been validated in controlled randomized studies.
It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention.
Angiotensin II (AII) is a potent vasoconstrictor peptide from the renin-angiotensin system in the kidney. The AII type 1 receptor (AT1R) is reportedly expressed in several tumors including renal cell carcinoma, and AII is involved in tumor angiogenesis. We p.o. administered the long-acting AT1R antagonist, candesartan (10 mg/kg), to the 16 days mouse renal cancer lung metastasis model to test the preventive effects in tumor metastasis. Pulmonary metastases of renal cancer showed prominent AT1R expression in both mice and humans, and candesartan treatment dramatically prevented lung metastatic nodules (14.9 +/- 1.8; P < 0.0001; n = 12) in mice along with the inhibition of neovascularization and vascular endothelial growth factor expression, compared with control metastatic mice (123.3 +/- 8.6; n = 13). Candesartan is widely used clinically, so it seems to be a reasonable therapy for patients with lung metastases of renal cell carcinoma.
Angiotensin II (Ang II) induces, through AT1, intracellular Ca(2+) increase in both normal and cancerous breast cells in primary culture (Greco et al., 2002 Cell Calcium 2:1-10). We here show that Ang II stimulated, in a dose-dependent manner, the 24 h-proliferation of breast cancer cells in primary culture, induced translocation of protein kinase C (PKC)-alpha, -beta1/2, and delta (but not -epsilon, -eta, -theta, -zeta, and -iota), and phosphorylated extracellular-regulated kinases 1 and 2 (ERK1/2). The proliferative effects of Ang II were blocked by the AT1 antagonist, losartan. Also epidermal growth factor (EGF) had mitogenic effects on serum-starved breast cancer cells since induced cell proliferation after 24 h and phosphorylation of ERK1/2. The Ang II-induced proliferation of breast cancer cells was reduced by (a) Gö6976, an inhibitor of conventional PKC-alpha and -beta1, (b) AG1478, an inhibitor of the tyrosine kinase of the EGF receptor (EGFR), and (c) downregulation of 1,2-diacylglycerol-sensitive PKCs achieved by phorbol 12-myristate 13-acetate (PMA). A complete inhibition of the Ang II-induced cell proliferation was achieved using the inhibitor of the mitogen activated protein kinase kinase (MAPKK or MEK), PD098059, or using Gö6976 together with AG1478. These results indicate that in human primary cultured breast cancer cells AT1 regulates mitogenic signaling pathways by two simultaneous mechanisms, one involving conventional PKCs and the other EGFR transactivation.
Angiotensin II (A-II) receptor (AT(1) receptor) blockers (ARB) are a class of antihypertensive agent. It is known that they suppress signal transduction pathways mediated by growth factors [e.g., epidermal growth factor (EGF)] through the AT(1) receptor in vascular endothelial cells. In the present study, we demonstrated that A-II activates the cell proliferation of prostate cancer as well as EGF. In addition, we showed that A-II induces the phosphorylations of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) in prostate cancer cells. In contrast, ARB was shown to inhibit the proliferation of prostate cancer cells stimulated with EGF or A-II, the mechanism of which is through the suppression of MAPK or STAT3 phosphorylation by ARB. Oral administration of ARB to nude mice inhibited the growth of prostate cancer xenografts in both androgen-dependent and androgen-independent cells in a dose-dependent manner. Microvessel density was reduced in xenografts treated with ARB, which means ARB inhibits the vascularization of xenografts. Expression of AT(1) receptor mRNA was examined by reverse transcription-PCR using 10 pairs of human prostate cancer and normal prostate tissues. AT(1) receptor expression in human prostate cancer tissue was higher (9 of 10 cases) than that in normal prostate tissue. These results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer, especially hormone-independent tumors.
The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power.
To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest.
A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004.
Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome.
Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with metastases detected at the time of diagnosis.
Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved.
interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.
Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II type I receptor (AT1R) antagonists are commonly used as a treatment for hypertension. Recent experimental and population studies have suggested that these agents may exert an inhibitory effect on malignancy, possibly through anti-angiogenic pathways. The aim of this study was to investigate the effect of an ACE-I (captopril) and an AT1R antagonist (irbesartan) in colorectal cancer liver metastases.
The effect of captopril and irbesartan on tumor growth was investigated in a mouse model using quantitative stereological and histological analysis. Tumor microcirculation was assessed by microvascular resin casting. A survival study was also carried out.
Both captopril and irbesartan markedly decreased tumor growth when compared to control (P = 0.003 and P = 0.004, respectively). However, there was no significant difference in survival or tumor necrosis for either of the drugs. Tumor microvasculature exhibited a reduction in central microvascular density, with constriction and tapering of vessels.
Captopril and irbesartan caused a marked reduction in volume of colorectal cancer liver metastases and caused changes in tumor microvasculature. However, there was no difference in percentage tumor necrosis or improvements in survival. Further investigation is needed to identify the mode of action of these agents.
The renin–angiotensin system and cancer: old dog, new tricks
- George
A.J. George, W.G. Thomas, R.D. Hannan, The renin-angiotensin system and cancer:
old dog, new tricks, Nat. Rev. Cancer 10 (11) (2010) 745.
- F Asgharzadeh
F. Asgharzadeh, et al.
Life Sciences 242 (2020) 117181