Table 1 Effect of RAAS inhibitors and their associated targets in various cancers

Ovarian cancer

Ang II/AT1R

Human epithelial ovarian cancer tissues

In ovarian cancer patients, AT1R could be associated with tumor angiogenesis and a poor prognosis.

[339]

Candesartan and PD123319

AT1R

- Human epithelial ovarian tumor tissues

- SKOV-3 and HRA cell line

- BALB/c mouse model of peritoneal carcinomatosis

- Ovarian cancer expresses AT1R, which is involved in angiogenesis and tumor growth.

- A promising approach to treating ovarian cancer may be AT1R blocking therapy.

[95]

losartan and captopril

PAX8

- OVCAR-4, OVCAR-8 and HEK293T cell lines

- Losartan and captopril can inhibit PAX8 expression and function. Therefore, they may be a suitable pharmacological target for various forms of HGSC.

[179]

losartan

Ang II and AT1R and MCS formation

- A2780 and Ovca429 cell lines

- The isogenic non-metastatic (NM) and highly metastatic (HM) cells

- NOD-SCID mouse

- Ang II increases MCS formation and rise peritoneal metastasis of epithelial ovarian cancer cells.

- By overexpression of SCD1, AT1R activation enhances lipid desaturation, which finally can lessen endoplasmic reticulum stress in MCS.

[183]

sPRR

− 197 primary epithelial ovarian cancer patients

- sPRR probably doesn’t have prognostic, predictive, or diagnostic value in epithelial ovarian cancer

[176]

Ang 1–7, Ang 1–9 and Ang 3–7

- OVPA8 cell line

- Peptides from RAS have the ability to regulate how nutrient-deprived tumors adapt to starvation.

- The availability of growth factors and nutrition has a significant impact on how angiotensin peptides affect cancer cells.

[340]

ACE

41epithelial ovarian cancer patients and 19 healthy controls

- serum ACE levels has been increased

- circulating ACE is probably related to pathobiologic process

[177]

losartan and CGP42112A

AT1R and AT2R

− 58 human epithelial ovarian cancer tissues

− 2774, A2780, PA-1, SKOV3ip1, HeyA8 cell lines

- Human umbilical vein endothelial cells (HUVEC)

Dual regulation of AT1R and AT2R, which inhibits angiogenesis and cancer cell survival, might be a potential for treating epithelial ovarian carcinoma.

[178]

losartan

AT1R

- SKOV3ip1 and Hey-A8 ovarian cancer cells

- orthotopic human ovarian carcinoma xenograft models

- mouse fibroblast (10T1/2)

- mice (Mus musculus), and rats (Rattus norvegcus)

losartan therapy can improve paclitaxel’s effectiveness

losartan can increase medication delivery and improve vessel perfusion.

losartan it can lower both the incidence and the volume of ascites produced.

[184]

Prostate cancer

Ang II and relaxin 2

- PNT1A cells

The development of some malignancies, particularly prostate cancer, may be influenced by the dysregulation of locally released peptide hormones including Ang II and relaxin 2.

[189]

recombinant adenoviruses encoding AT2R (Ad5-CMV-AT2R-EGFP)

AT1R and AT2R

- DU145 cell lines

- BALB/c nude mice

The findings demonstrated that AT2R overexpression can prevent prostate cancer tumor growth in vivo by preventing tumor cell proliferation and triggering apoptosis. The gene AT2R has the potential to be helpful in prostate gene therapy.

[185]

an AT2R agonist (C21)

AT2R

- LNCaP cells

- transgenic rat for adenocarcinoma of prostate (TRAP) model

A potential new chemo preventive drug against human prostate cancer is AT2R agonist.

[186]

fimasartan, losartan, eprosartan and valsartan

AT1R

PC-3, DU-145 and LNCapLN3 cell lines

Prostate cancer cells may exhibit anti-metastatic action and autophagy-associated cell death when exposed to ARBs.

[189]

candesartan

AT1R and Caveolin-1

- Metastatic prostate adenocarcinoma cells (PC-3)

- The mRNA and protein levels of caveolin expression may be regulated by candesartan.

- growth inhibition of metastatic PC3 cell line

[341]

olmesartan

AT1R, ACE and Ang I/II

- DU145 and LNCaP cells

- human prostate cancer cell lines

- prostate stromal cells (PrSCs)

Prostatic RAS is overexpressed in hormone-resistant prostate cancer tissue, and different types of hormonal stimulation affect the expression of its components.

[342]

Ang 1–7

Ang 1–7

- Human PC3 prostate cancer cells

- SCID mice

For advanced prostate cancer, Ang 1–7 may function as an anti-metastatic agent and anti-angiogenic.

[343]

Ang 1–7

Ang 1–7

- LNCaP human prostate cancer cells

- Male athymic mice

A potential anti-angiogenic therapy for prostate cancer may be Ang 1–7.

[344]

Ang 1–9 and Ang 3–7

AT1R

AT2R

AT4R

Mas receptor

PNT1A cell line

Ang1-9 and Ang3-7 have opposite effects

Ang1-9: cause cell divisions, increase cell motility, and stimulate the expression of genes including VEGF, HIF-1, VIM, and REL Ang3-7: exhibit no mitogenic action

[193]

Ang 1–9 and Ang 3–7

AT1R

AT2R

AT4R

Mas receptor

LNCaP cell line

PC3 cell line

Ang 1–9 and Ang 3–7 might alter the overall number of steroid receptors in aggressive prostate cells.

the switch from hormone-dependent prostate cancer to hormone-refractory illness may be facilitated by Ang 1–9 and Ang 3–7

[194]

Breast cancer

Candesartan

AT1R

Xenograft mice model

Inhibition of tumor growth and angiogenesis

[345]

Ibesartan

AT1R

BC cell line

Suppression of cell proliferation

[346]

Olmesartan

AT1R

BC cell line

Apoptosis induction

[347]

Losartan

AT1R

Mouse model

Suppression of tumor cell proliferation, Reduction of inflammatory cytokines.

[348]

BC Cell line

Reverse the Ang II-induced cancer cell proliferation and VGEF-A upregulation, Reduction in cell adhesion and invasion

[198, 345]

4T1 and EMT6 murine TNBC cell lines

Improves the Antitumor Efficacy of Dox-L Chemotherapy,

Combination Therapy Involved α-PD1 Immunotherapy Alleviates Primary Tumor Burden and Lung Metastases

[240]

mouse (E0771 and 4T1 models)

Reduces stromal fibrosis, signalling

Reduced solid stress, increase blood perfusion in tumours, enhance drug and oxygen delivery.

[77]

Captopril

ACE1

TAM resistant BC cell line

Prevention of TAM resistant cells

[349]

BC cell line with adipocyte-CM exposure

Reduction of cancer growth and inflammation in TME

[350]

BC cell line

Inhibition of TF and VEGF expression

[351]

Perindopril

ACE1

Mouse tumor xenograft and corneal micropocket model

Inhibition of tumor growth and angiogenesis

[352]

ACEI and / or ARBs

ACE 1and / or AT1R

Human studies (Meta-Analysis)

Decreased breast cancer risk with long-term ACEI /ARB use

[353]

Human studies: Retrospective study

No association with ACEI /ARB use and with disease free or overall survival

[242]

higher incidence of invasive lobular carcinoma subtype

[354]

CRC

Telmisartan

AT1

In vitro

Inhibit cell proliferation, G0/G1 cell cycle arrest,

[254]

Captopril

ACE

Mouse Model

Reduce EMT and invasive phenotype, Reduced tumor growth, reduction in volume of colorectal cancer liver metastases

[169, 355]

Ibesartan

AT1R

Mouse Model

Reduced tumor growth, reduction in volume of colorectal cancer liver metastases

[169]

Candesartan

AT1R

In vitro / CRC mouse models

Inhibition of CRC cell growth and migration, enhanced necrosis in CRC cells and tumors

[356]

Valsartan

AT1R

In vitro/CRC mouse models

Inhibition of tumor cell growth, Induction of apoptosis, Inhibition of cell migration, ameliorate inflammation

[357]

Losartan

AT1R

Xenograft Model

Inhibition of tumor growth, migration and angiogenesis, increase pro-inflammatory cytokines

[358]

LP2

AT2R

Xenograft model

Apoptosis in patient-derived xenografts of colorectal carcinoma, synergism demonstrated in combination of LP2 with 5-FU and the EGFR inhibitor erlotinib

[251]

ACEis/ARBs

ACE1/AT1R

Human studies: Retrospective cohort study

association with a lower colorectal cancer risk in a duration-response manner

[359]

Human studies: Cohort analysis of SEER-Medicare database

ACE inhibitors associated with decreased mortality

[257]

Human studies : Retrospective study

ACEI/ARB + BB exposure was associated with decreased mortality compared to unexposed individuals, decrease in cancer progression, decrease cancer-related hospitalizations

[259]

ACEI/ARB treatment may reduce tumor recurrence in left-sided CRC and early-stage CRC.

[260]

Gastric cancer

CandesartanTelmisartan

AT1R

Human GC cell line

Reduce cellular proliferation

[266]

Candesartan

Xenograft Model

Inhibition of Tumor growth, Suppression of EMT and fibrosis

TCV-116

AT1R

Xenograft Model

Inhibition of tumor growth, reduce VEGF

[360]

Olmesartan

AT1R

N87 and MKN45 cell lines (Human GC cell line)

significant decrease in invasive ability of cancer cells

[263]

RAAS inhibitors

ACE1/AT1R

Human studies: Cohort studies

Lower incidence of GC rate

[361]

Pancreatic cancer

Losartan

AT1R

Orthotopic PDAC in mice

Increase drug uptake and functional microvasculature, Inhibition of Cell proliferation and VEGF expression, improve survival rate

[362, 363]

A Phase 2 Clinical Trial

(Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer)

Prolonged progression-free and overall survival.

[243]

Captopril

ACE1

In vitro and In vivo studies

Targeted delivery of captopril to the CAFs, significantly down-regulated the deposition of ECM by blocking the TGF-β1-Smad2 and consequently enhance the liposome-encapsulated chemotherapeutic agent gemcitabine.

[364]

Irbesartan

AT1R

In vitro and In vivo studies

effectively reduced chemoresistance in PDAC

[292]

Telmisartan

AT1

In vitro

Inhibit the human PDAC cell pro;iferation by cell cycle arrest,

The miRNA expresseion profile was markedly altered

[365]

Orthotopic PDAC mice model

increased vascular perfusion and reduced hypoxia,

[366]

Wistar Bonn/Kobori (WBN/Kob) rat

Prevented the development of chronic pancreatitis and fibrosis.

[276]

Human studies: Retrospective analysis

longer overall survival in PDAC patients with non-metastatic disease and resected PDAC patients, improve clinical outcomes in patients with advanced pancreatic cancer in combination with Gemcitabine

[367,368,369]

A population study

Improve survival

[293, 370]

Hepatic cancer

Candesartan

AT1R

Hepatic carcinoma cell line

Inhibition of proliferation

[306]

Telmisartan

AT1R

non-alcoholic steatohepatitis (NASH) rats

Prevent hepatocarcinogenesis through inhibition of angiogenesis

[371]

Irbesartan

AT1R

Xonegraft model

Inhibition of HCC growth and Metastasis, Weaken adhesion to endothelial cells

[311]

Losartan

AT1R

diethylnitrosamine-induced hepatocellular carcinoma in mice

Decrease cell migration, Metastasis, Inhibition of Neovascularization

[372]

Fosinopril

ACE

Perindopril

ACE

Azilsartan

AT1R

hepatocellular adenocarcinoma cell line

Induce cell apoptosis

[373]

Losartan

AT1R

Mouse model of HCC

reduced liver and peritumoral fibrosis ,

lenhance anti-PD-1-triggered HCC regression in

[374]

Esophageal cancer

Telmisartan

AT1R

EAC Cell lines

Inhibition of proliferation and cell cycle arrest

[332]

Xenograft Model

Inhibition of tumor growth

Benazepril

ACE

Xenograft Model

Inhibition of tumor growth and angiogenesis

[335]

ACEi and/ or ARBs

ACE/AT1R

Human studies: a nested case control study

Decrease the risk of ESCC and EAC in high daily doses

[375]