Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments

Perini, Marcos Vinícius; Dmello, Rhynelle S.; Nero, Tracy L.; Chand, Ashwini L.

doi:10.1016/j.pharmthera.2020.107527

Cited by 41 publications

(44 citation statements)

References 173 publications

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“…From a therapeutic point of view, the pathology of hypertensive renal disease can be attenuated by reduction of systemic and preglomerular blood pressure load, as well as regulation of cellular and molecular pathways that mediate tissue injury (Bidani and Griffin, 2004). In this context, AT1R antagonists are important antihypertensive agents mainly when combined with diuretics such as hydrochlorothiazide (HCTZ) or angiotensin converting enzyme (ACE) inhibitors (Ueda et al, 2012;Perini et al, 2020). Thus, investigating the effects of AT1R antagonists on the deleterious intrarenal effects induced by Ang II seems to be relevant for scientific and clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron

et al. 2021

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High plasma angiotensin II (Ang II) levels are related to many diseases, including hypertension, and chronic kidney diseases (CKDs). Here, we investigated the relationship among prolonged Ang II infusion/AT1 receptor (AT1R) activation, oxidative stress, and endoplasmic reticulum (ER) stress in kidney tissue. In addition, we explored the chronic effects of Ang II on tubular Na+ transport mechanisms. Male Wistar rats were subjected to sham surgery as a control or prolonged Ang II treatment (200 ng⋅kg–1⋅min–1, 42 days) with or without losartan (10 mg⋅kg–1⋅day–1) for 14 days. Ang II/AT1R induced hypertension with a systolic blood pressure of 173.0 ± 20 mmHg (mmHg, n = 9) compared with 108.0 ± 7 mmHg (mmHg, n = 7) in sham animals. Under these conditions, gene and protein expression levels were evaluated. Prolonged Ang II administration/AT1R activation induced oxidative stress and ER stress with increased Nox2, Nox4, Cyba and Ncf1 mRNA expression, phosphorylated PERK and eIF2α protein expression as well as Atf4 mRNA expression. Ang II/AT1R also raised Il1b, Nfkb1 and Acta2 mRNA expression, suggesting proinflammatory, and profibrotic effects. Regarding Na+ tubular handling, Ang II/AT1R enhanced cortical non-phosphorylated and phospho/S552/NHE3, NHE1, ENaC β, NKCC2, and NCC protein expression. Our results also highlight the therapeutic potential of losartan, which goes beyond the antihypertensive effect, playing an important role in kidney tissue. This treatment reduced oxidative stress and ER stress signals and recovered relevant parameters of the maintenance of renal function, preventing the progression of Ang II-induced CKD.

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Section: Discussionmentioning

confidence: 99%

Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron

et al. 2021

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“…Down-regulation of c-myc is likely to be one mechanism through which captopril and other RASi are capable of attenuating tumor growth and progression. RASi are commonly used to treat hypertension and cardiac failure; however, they also have a wide range of effects which are not limited to the cardiovascular system [ 29 , 48 ]. RASi have established roles in multiple processes influencing cancer progression, including angiogenesis, extracellular matrix remodeling, cellular proliferation, EMT and immunomodulation [ 27 , 29 , 30 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, inhibition of RAS was associated with a reduction in cancer cell migration and reduced Zeb-1 expression in vitro [ 26 ]. Collectively, there is growing molecular and functional evidence that inhibitors of the classical RAS reduce tumor growth and progression and might augment cancer therapies [ 27 , 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis

Riddiough

Fifis

Walsh

et al. 2021

Cancers

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(1) Background: Recent clinical and experimental data suggests that the liver’s regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/β-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.

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“…Determining the dose of drug used in the tumor-bearing mouse model and establishing a stable proteinuria model related to AADs Because captopril was reported to promote tumor growth in an immunogenic model and decrease the survival of immunogenic mice in a dose-dependent manner [33], we established two mouse subcutaneous tumor models, the immunogenic C57BL/6 mouse model with Hep1-6 cells and the immunode cient BALB/c nude mouse model with MHCC-97H cells to verify this effect. To generalize the role of ACEIs, we chose three representative drugs: captopril containing thiol, enalapril without thiol and fosinopril containing phosphorus [34]. After tumors were established (Figure 2, a and e), the mice received different doses of ACEIs [vehicle, high-dose captopril (60 mg/kg/day), low-dose captopril (30 mg/kg/day), highdose enalapril (60 mg/kg/day), low-dose enalapril (30 mg/kg/day), high-dose fosinopril (10 mg/kg/day) and low-dose fosinopril (5 mg/kg/day)], which were based on the low and high doses used in humans according to a body surface area dose conversion method, as reported in previous literature [19,35,36].…”

Section: Resultsmentioning

confidence: 99%

Angiotensin-Converting Enzyme Inhibitors Have Adverse Effects in Anti-Angiogenesis Therapy for Hepatocellular Carcinoma

et al. 2020

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Background: Currently, most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria caused by anti-angiogenic drugs (AADs) according to diabetic nephropathy guidelines or expert recommendations. However, the e cacy ACEIs and potential cancer promoting effect are controversial. This study aimed at con rming whether ACEIs are bene cial in anti-angiogenesis therapy for hepatocellular carcinoma. Methods: In clinic, we observed the impact of ACEIs on AADs during the treatment of hepatocellular carcinoma. Next, we established different tumor-bearing mouse models to con rm that whether ACEIs have any effect on the anti-cancer e cacy and proteinuria side effects of AADs. Further, we con rmed the relevant mechanism in vivo. Results: Our clinical data have shown that some hepatocellular carcinoma (HCC) patients experienced tumor progression by ACEIs administration for the treatment of hypertension or proteinuria caused by AADs. We have con rmed that in different tumor-bearing mouse models, ACEIs did not delay the appearance of proteinuria or alleviate proteinuria caused by AADs but compromised the anticancer e cacy of AADs. This effect is unrelated to a change in the VEGF signaling pathway. Our data showed that the combination of ACEIs and AADs ared the production of kidney-derived erythropoietin (EPO). In turn, EPO compromises the anti-angiogenic effects of AADs and decreases antitumor activity. Conclusions: For the treatment of proteinuria caused by AADs, ACEIs have no e cacy but promote drug resistance. Kidney-derived EPO is mainly responsible for ACEIs induced anti-angiogenesis resistance.

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Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments

Cited by 41 publications

References 173 publications

Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron

Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron

Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis

Angiotensin-Converting Enzyme Inhibitors Have Adverse Effects in Anti-Angiogenesis Therapy for Hepatocellular Carcinoma

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