by Dr. Marian Laderoute

June 14, 2023

from HERV-K102 Website

 

 

 

 

For PDF click above image...

 

 


If you think Big Pharma

had good reasons to censor Ivermectin

during COVID-19

how about now when we know

 it is likely effective against

all chronic diseases associated with aging?




Dr. Paul Marik recently quoted a prospective clinical trial where the participants were given 4000 international units of Vitamin D, omega 3's and told to exercise and the risk of cancer dropped 50%.
 

 

 


In another post, Dr. Marik says,

it is highly unlikely cancer is genetically determined...

I wanted to talk about both in this post.

In July 1994, I published a new theory of cancer in Molecular Carcinogenesis which implied while tumors were genetically determined, the malignant nature of tumors (i.e., the thing we call cancer) was not. 1

This notion that malignancy was a phenotype and not a genotype was heretical at the time and so the paper was ignored (only the editors of Molecular Carcinogenesis and myself were excited).

 

It was an exciting idea because it meant one can control the malignant potential of tumors pharmacologically. No more need for slash and burn, which I have always regarded as barbaric.

However, subsequently it became widely accepted that the malignant phenotype of cancers called 'epithelial mesenchymal transition' (EMT) was real. 2

 

So I was vindicated, although it seems no one noticed except for myself.

The reason I had proposed cancer as a phenotype was that I had just finished the characterization of the 67 kD alpha-fetoprotein (AFP) receptor for my Ph.D. thesis. 3-6

 

The AFP receptor (AFPr) 4 was expressed on macrophages 3,6 and highly over-expressed on the common cancers the adenocarcinomas (breast, prostate, lung, colon, etc) 3,5 implying a dual role in immuno-suppression of the host and in tumor malignant potential. In fact I wrote the theory to explain how immuno-suppression of the host relates to tumor malignant potential.

AFP was the very first immunosuppressive factor described (1974) and the first tumor marker discovered (1963).

 

We were first to show it prevented cell lysis (apoptosis) of macrophages in 1994 6 where the data had also been presented in the Ph.D. thesis by 1991.

It is now well established that AFP contributes to the malignant phenotype through the PI3K/Atk /mToR pathway, the same one conferred by oncogenic HER-2/nu (ERB2).
 



Figure 1.

From Giannelli G et al, Cancer Research 2014. 7

AFP is recognized as a malignancy progression factor

 in a very common cancer in the world,

hepatocellular carcinoma (HCC)

which is often associated with a viral origin.



Thus, the malignant potential of tumors known as cancer was amenable to pharmacological intervention and by entities that inactivate AFP.

AFP exists in active and inactive states.

 

Things that bind to and inactivate AFP (zinc, DHEA, flavonoids etc) are entities that may help promote innate immunity (of macrophages) and which also diminish the malignant potential of tumors.

At the time I called this malignant phenotype of cancers "anti-cellular senescence". 1

 

This was because the tumor was refractory to new signaling because AFP binding to the AFPr on tumors blocked incoming signals. So it seemed the tumor did not age. {Note anti-aging at the cellular level is associated with aging at the whole host level.}

While the malignant phenotype is now recognized as 'epithelial-mesenchymal transition' (EMT), fortunately Dr. Robert Weinberg has included the phenotype of blocking senescence in EMT 8 ie., a phenotype involving anti-cellular senescence (whew!).

Then in 2015, I wrote the new immuno-senescence paradigm of macrophages published in Discovery Medicine (Figure 2) which attempts to explain the cause of chronic illness associated with aging including diseases such as cancer and cardiovascular diseases. 9

Noteworthy, the immuno-senescence of macrophages involves immuno-suppression AND paradoxically the uncontrolled release of pro-inflammatory factors such as IL-6, TNF-alpha and IL-1beta. It is the inflammation that contributes to the start of chronic diseases.

 

This would be exacerbated by ongoing infections due to the immuno-suppression.

AFP by binding the 67 kD AFPr, induces immunosuppression and prevents the down-modulation of the inflammatory factors. It is believed the inflammation is through activation of NFKB1 (see later).
 



Figure 2.

The New Immunosenescence Paradigm of Macrophages
was defined as the failed (lytic) release of

protector HERV-K102 particles from foamy macrophages.

HERV-K102 is a non-pathogenic, protector foamy retrovirus

 unique to humans which renders macrophages foamy

 (the particles accumulate in vacuoles in

the cytoplasm giving the cells a foamy appearance).

 When the DHEA/cortisol ratio is low, there is a higher risk

of immunosenescence upon exposures to virus

due to inadequate levels of DHEA to bind and inactivate AFP.

We reported in 1994 that

AFP blocks apoptosis of macrophages [6].



Subsequently I validated this paradigm specifically for explaining the initiation and progression of cardiovascular disease. 10 (i.e., it is not elevated cholesterol but elevated stress does increase cholesterol so increases in cholesterol are a sign of stress).

P53 along with TGF-beta, represses AFP expression, and p53 is a tumor suppressor commonly deleted or at least dysfunctional in tumors/cancers. 11

ZBTB20 is a zinc finger credited with post-natal down-regulation of AFP. However, when functional p53 is absent, it upregulates AFP. 12

Did you know that ZBTB20 is required for the induction of NFKB1 13 such as when SARS-CoV-2 infects foamy macrophages in vivo by antibody dependent enhancement of infection (ADE) 14 which contributes to cytokine storm?

 

AFP is significantly upregulated by SARS-CoV-2 infection at the protein and mRNA level in cell lines. 15
 




Referring back to Figure 2, AFP antagonists reverse and prevent immuno-senescence.

 

Immuno-senescence causes age-associated chronic diseases. 9,10

 

This means AFP antagonists like zinc, flavonoids, DHEA/7ketoDHEA, Vitamin D over 60 ng/ml, and now also Ivermectin [16] are likely AFP antagonists which are therefore, predicted to reduce the risks of age-associated chronic illness including cancer and cardiovascular disease, etc..

There are now in addition to many reports on how Ivermectin behaves as a potent antiviral, emerging evidence for its reversion of the malignant phenotype particularly by inducing apoptosis 17 and blocking metastasis. 18

So if you think the war on Ivermectin is over, in fact, it is just getting STARTED...!




REFERENCES

  1. Laderoute MP. A new perspective on the nature of the cancer problem: anti-cellular senescence. Mol Carcinog. 1994 Jul;10(3):125-33. doi: 10.1002/mc.2940100303.
     

  2. Zhang Y, Weinberg RA. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018 Aug;12(4):361-373. doi: 10.1007/s11684-018-0656-6.
     

  3. Laderoute MP. The Characterization of a Novel, Widespread, PNA-Reactive Tumor Associated Antigen: the Alpha-fetoprotein Receptor/Binding Protein. Ph.D. Thesis. The University of Alberta. Canada 1991, pp 256. https://era.library.ualberta.ca/items/6f548eb6-49a2-456c-b472-41f68976077f.
     

  4. Moro R, Tamaoki T, Wegmann TG, Longnecker BM, Laderoute M. Monoclonal antibodies directed against a widespread oncofetal antigen: the alpha-fetoprotein receptor. Tumor Biology 1993 14 (2):116-130. Https: //doi.org/10.1159/000217864.
     

  5. Laderoute M, Willans D, Wegmann T, Longenecker M. The identification, isolation and characterization of a 67 kilodalton, PNA-reactive autoantigen commonly expressed in human adenocarcinomas. Anticancer Res. 1994 May-Jun;14(3B):1233-45.
     

  6. Laderoute MP, Pilarski LM. The inhibition of apoptosis by alpha-fetoprotein (AFP) and the role of AFP receptors in anti-cellular senescence. Anticancer Res. 1994 Nov-Dec;14(6B):2429-38.
     

  7. Giannelli G, Villa E, Lahn M. Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma. Cancer Res. 2014 Apr 1;74(7):1890-4. doi: 10.1158/0008-5472.CAN-14-0243.
     

  8. Weinberg RA. Twisted epithelial-mesenchymal transition blocks senescence. Nat Cell Biol. 2008 Sep;10(9):1021-3. doi: 10.1038/ncb0908-1021.
     

  9. Laderoute MP. A new paradigm about HERV-K102 particle production and blocked release to explain cortisol mediated immunosenescence and age-associated risk of chronic disease. Discov Med. 2015 Dec;20(112):379-91.
     

  10. Laderoute M. The paradigm of immunosenescence in atherosclerosis-cardiovascular disease (ASCVD). Discov Med. 2020 Jan-Feb;29(156):41-51.
     

  11. Wilkinson DS, Ogden SK, Stratton SA, Piechan JL, Nguyen TT, Smulian GA, Barton MC. A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol. 2005 Feb;25(3):1200-12. doi: 10.1128/MCB.25.3.1200-1212.2005.
     

  12. To JC, Chiu AP, Tschida BR, Lo LH, Chiu CH, Li XX, Kuka TP, Linden MA, Amin K, Chan WC, Bell JB, Moriarity BS, Largaespada DA, Keng VW. ZBTB20 regulates WNT/CTNNB1 signalling pathway by suppressing PPARG during hepatocellular carcinoma tumourigenesis. JHEP Rep. 2020 Dec 19;3(2):100223. doi: 10.1016/j.jhepr.2020.100223.
     

  13. Liu X, Zhang P, Bao Y, Han Y, Wang Y, Zhang Q, Zhan Z, Meng J, Li Y, Li N, Zhang WJ, Cao X. Zinc finger protein ZBTB20 promotes Toll-like receptor-triggered innate immune responses by repressing IκBα gene transcription. Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11097-102. doi: 10.1073/pnas.1301257110.
     

  14. Ren X, Wen W, Fan X, et al. COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell. 2021 Apr 1;184(7):1895-1913.e19. doi: 10.1016/j.cell.2021.01.053.
     

  15. Appelberg S, Gupta S, Svensson Akusjńrvi S, et al. Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg Microbes Infect. 2020 Dec;9(1):1748-1760. doi: 10.1080/22221751.2020.1799723.
     

  16. Laderoute M. Ivermectin may prevent and reverse immunosenescence by antagonizing alpha-fetoprotein and downmodulating PI3K/Akt/mTOR hyperactivity. Open Heart. April 29, 2021. https://openheart.bmj.com/content/8/1/e001655.responses#Ivermectin-may-prevent-and-reverse-immunosenescence-by-antagonizing-alpha-fetoprotein-and-downmodulating-pi3k-akt-mtor-hyperactivity.
     

  17. Tang M, Hu X, Wang Y, Yao X, Zhang W, Yu C, Cheng F, Li J, Fang Q. Ivermectin, a potential anticancer drug derived from an antiparasitic drug. Pharmacol Res. 2021 Jan;163:105207. doi: 10.1016/j.phrs.2020.105207.
     

  18. Jiang L, Sun YJ, Song XH, Sun YY, Yang WY, Li J, Wu YJ. Ivermectin inhibits tumor metastasis by regulating the Wnt/β-catenin/integrin β1/FAK signaling pathway. Am J Cancer Res. 2022 Oct 15;12(10):4502-4519.