Losartan can dissolve peritumoral collagen, significantly increase the effectiveness of chemo, reduce ascites, and block intratumoral blood vessel formation. Retrospective analyses show that losartan users have 30 months longer overall survival compared to patients with other blood pressure lowering drugs.
Tumor stroma – the unknown quantity
I became aware of the potency of sartans when I was researching STROMA – TUMOR interactions.
What is little known: Tumor cells enslave the surrounding fibroblasts via microvesicles (Study 2019, Review 2018).
The fibroblasts near the tumor have to switch to the Warburg glycolysis metabolism and the tumor imports the fibroblastic lactic acid as an additional energy source in order to burn it oxidatively.
This is called the “reverse Warburg mechanism“. These tumors – around 30% – are particularly malignant and resistant to therapy, and cannot be particularly influenced by a ketogenic diet.
Apropo ketogenic – contraindicated in prostate cancer
just like prostate carcinoma, which lives mainly from fat – which is why we don’t do a sugar PET but a fatty acid PET – and really flourishes with a ketogenic diet (Retzek, own observation, J.Epidemiol.2012, ClinOncol 1998 and many more) – only fish oil improves the prognosis of prostate cancer.
The following study electrified me, as a proven blood pressure medication that has been prescribed millions of times can have a significant impact on the cancer process:
Ovarian cancer: 30 month extension of overall survival with losartan in addition to chemo
Losartan increases chemo effectiveness and reduces ascites in ovarian cancer by normalizing the tumor stroma
In ovarian cancer patients, survival time correlates with the extent of tumor fibrosis, which is driven by angiotensin.
In the study, 2 OvCa tumor models were created and treated with losartan, resulting in the following findings:
- Losartan increases the efficiency of paclitaxel treatment, by normalizing the tumor microenvironment, which leads to improved blood flow and chemotherapy delivery.
- Losartan reduces the matrix through antifibrotic miRNA, which is also considered a marker for chemo-resistance
- although losartan alone has no effect on tumor load, it reduces the amount of ascites
- our retrospective study shows that patients with ovarian carcinoma and sartan therapy – in addition to standard chemo have a 30-month longer OS (survival), compared to patients with other antihypertensives.
Survival data are drastically dependent on the angiotensin system!
Without the AT1R we have practically complete curability of the tumor. In addition, as shown below, the AT1R induces the expression of VEGF.
Given these data from BMJ 2006 FullTextPDF, it is interesting that this has hardly been addressed clinically in the form of further studies.
how does it work?
the connections from a summary of many studies
The summary is complicated and not easy for laypeople to understand:
Angiotensin II is a blood pressure regulating hormone that is produced in the kidneys and the circulatory system. The release from the angiotensinogen is caused by ACE.
There are angiotensin II receptors type 1 = AT1R and type 2 = AT2R (these are nuclear) which have opposing effects on blood flow andand blood pressure and much more.
The ratio between AT1R / AT2R is crucial for survival time
- AT1R – activates the cancer and the AT1R blockers “sartans” inhibit cancer.
- AT1R is upregulated in cancer, the stronger the regulation, the worse the prognosis
- AT1R triggers the VEGF system and multiple cancer-promoting cytokines, but does not affect cancer immunology. Inhibition of At1R also reduces VEGF
- nuclear AT2R – inhibits cancer, so-called AT2R – AGONISTS are then cancer-inhibiting
- Main effect is in prophylaxis and as an adjuvant to chemo / radiation, less as a direct tumor-static agent
Colorectal carcinoma – inhibition of IGF-1 and VEGF
Suppression of the AT2 receptor by sartans was able to reduce the development of tumors and polyps in the colon as well as the formation of metastases. This effect is mediated by inhibition of angiogenesis / VEGF and IGF-1. CurPharmDes.2019
It would be exciting to inhibit IGF-1 by Losartan, because then the influence of protein food on tumor progression could be decoupled.
Squamous cell carcinoma in the mouth – adjuvation of 5FU chemo
Angiotensin receptors are clearly linked to the progression of “Oral Squamous Carcinoma”, as shown by the study of 23 different carcinomas.
It can be shown that the effect of 5FU can be increased by Losartan. Oncotarget 2018
in the mouse model for breast cancer, tumor formation and the pathogenicity of the tumor can be inhibited
Breast cancers with a poor prognosis have an upregulation of AT1R
Mice get breast cancer induced by chemicals. Losartan inhibits 20% of this. and also reduces tumor load and progression by inhibiting proliferation, IL-6, TNF-a, but has no effect on MAF / TIL …. Study 2017
AT1R in breast cancer stimulates mobility and metastasis
via angiotensin II –> AT1R leads to the activation of PIK3/AKT (–> mTOR) and NFkB, and several matrix metalloproteinases are also expressed. All of this leads to a significant activation of the mobility and metastasis ability of the cells. Study 2014
Pancreatic carcinoma
Angiotensin II upregulates VGEF
As early as 2008, we found out: AT1R and VEGF are upregulated and expressed together in cancer cells, AT1R is a driving force here. If AT1R is blocked with sartans, VEGF is also reduced.
Apoptosis induced by Losartan independently of (mutated) p53
Study 2010 shows that angiotensin II receptor blockers have a direct pro-apoptotic effect on cancer cells, not just indirectly via blood flow inhibition. This also applies to several pancreatic cell models that have mutated p53.
No survival time extensions in mouse HCC due to ACE / sartans
Sartans or ACE inhibitors alone are not enough, shows this study from 2018. The above studies are all chemo-adjuvation studies in which drastic OLT extensions were achieved with chemo + losartan.
However, in contrast to this is the following mouse study ToxicLett2018, in which several sartans prevented HCC from growing further, the mechanism is the reduction of NFkB –> TGF-ß TNF-alpha –> VEGF and MMP2
Losartan cannot inhibit human leukemia cells
Losartan had no effect, but another AT2R blocker ANG1-7 was able to significantly block the growth of the leukemia cells. Study 2018
Gastro-esophageal cancer patients – survival improved in AT receptor blocker users
5100 patients, 360 of whom used an AT receptor blocker. An improvement in survival (moderate but statistically significant) was observed. Dose-dependent and time-dependent – with 2 years of losartan, the effect was 0.42 Study 2018
Conclusion
The AT1R mechanism offers a clear, direct and causal connection with
- Cancer development
- Cancer response to chemotherapy
Without chemotherapy, the drugment probably makes little sense, but with chemotherapy and radiation it leads to a significant increase in effectiveness, especially for ovarian cancer there is clear clinical data that indicates an OLT benefit of 30 months!
Whether ACE inhibitors also help here has yet to be determined, I have found initial indications (Study 2015)
In the “Retzek Protocol” we will be using the blood pressure medication losartan in addition to chemotherapy for the cancers described: mouth, colon, ovary, stomach, esophagus.
For ovarian carcinoma please read the article about propranolol and tripling survival time!
About angiotensin metabolism
from a short review about angiotensin metabolism Oncotarget 2017 Fulltext
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