Losartan improves the therapeutic effect of metronomic cyclophosphamide in triple negative mammary cancer models

Abstract

Metronomic chemotherapy refers to the minimum biologically effective doses of a chemotherapy agent given as a continuous regimen without extended rest periods. Drug repurposing is defined as the use of an already known drug for a new medical indication, different from the original one. In oncology the combination of these two therapeutic approaches is called "Metronomics". The aim of this work is to evaluate the therapeutic effect of cyclophosphamide in a metronomic schedule in combination with the repurposed drug losartan in two genetically different mice models of triple negative breast cancer. Our findings showed that adding losartan to metronomic cyclophosphamide significantly improved the therapeutic outcome. In both models the combined treatment increased the mice's survival without sings of toxicity. Moreover, we elucidated some of the mechanisms of action involved, which include a decrease of intratumor hypoxia, stimulation of the immune response and remodeling of the tumor microenvironment. The remarkable therapeutic effect, the lack of toxicity, the low cost of the drugs and its oral administration, strongly suggest its translation to the clinical setting in the near future.

Cancer-associated fibroblasts: Origin, function, imaging, and therapeutic targeting

“…6d-f) [335]. This was also confirmed with different pre-clinical models [336][337][338]. The effect was attributed mainly to the high intratumoral distribution of losartan compared to other angiotensin inhibitors such as candesartan.…”

Synergy of Losartan and chemotherapy for patients with cholangiocarcinoma: A propensity score-matched analysis

“…Generally, the AngII/AGTR1 axis is considered to promote the formation of immunosuppressive microenvironments and favor tumor growth ( 33 , 34 ). However, there are also conflicting reports suggesting potential tumor type specific differences ( 19 , 35 , 36 ). Therefore, we first screened patients with CCA from the clinical database of Department of General surgery, First Affiliated Hospital of Jinzhou Medical University, and then divided them into patients with losartan and patients without losartan combined with the treatment of adjuvant chemotherapy.…”

“…Losartan is an FDA-approved antihypertensive agent that blocks AGTR1 (15)(16)(17). Several studies have reported the synergy of losartan with chemotherapy across numerous tumors (15,(18)(19)(20). However, no report investigated the effect of losartan on chemotherapy for patients with CCA, which is the overarching objective of this study…”

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

“…The heterogeneity in the vascular perfusion within the tumor arises as a result of the formation of abnormal tumor vessels, which leak and can be compressed by both cancer and stromal cells (e.g., desmoplastic tumors). The strategies to decrease tumor hypoxia through vascular normalization and normalization of cancer-associated fibroblast/extracellular matrix could improve the outcome of therapies [9][10][11][12][13]. In addition to the vascular network, other sources of heterogeneity and plasticity in the tumor microenvironment are the immune-infiltrated cells and the cancer-associated fibroblasts (CAFs) [1,14], which could have a dual role in tumor progression and metastasis [15].…”