2nd Smartest Guy in the World reviewed a substack by Makis (below) that's staggering as it relates to potent role of IVERMECTIN (zinc ionophore) in reducing cancer risk (vaccine-induced TURBO cancers)

2nd smartest reviewed Ivermectin in Defeating Cancer and Other Common Chronic Diseases of Aging; powerful anticancer properties of Fenbendazole; Makis does superb scholarship here on IVM & cancer

IVERMECTIN and CANCER, it has at least 15 anti-cancer mechanisms of action. Can Ivermectin Treat COVID-19 mRNA Vaccine Induced Turbo Cancers? - 9 Ivermectin papers reviewed

Ivermectin May Defeat Cancer and Other Common Chronic Diseases of Aging

‘2nd Smartest Guy in the World substack:

PetDazole: Pharmaceutical Grade Pure Fenbendazole

2ND SMARTEST GUY IN THE WORLD

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JUN 6

Just like they went after one of the very best cures for PSYOP-19 in Ivermectin… …the Medical Industrial Complex does not want the truth to come out about a powerful cancer cure in Fenbendazole. Thanks to the deployment of the DEATHVAX™, we are now seeing parabolic increases in “turbo cancers.” Those responsible for these slow kill bioweapon injections…

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I also mentioned in passing that one of reasons Ivermectin was so viciously maligned and suppressed was that if society were taking it to cure PSYOP-19 one of the side effects would be “sudden” plummeting cancer rates, and thus BigPharma et al. went all out to destroy this Nobel prize miracle drug.

What would happen if one did a combination therapy for both the prevention and treatment of cancer using BOTH Ivermectin and Fenbendazole? The synergistic pairing would be far more effective than just using one of these miraculous drugs.

For many years now the cure for cancer was in plain sight right in front of everyone all this while, yet society was socially engineered to mindlessly “Trust the Science” such that they would undergo incredibly expensive (read: exorbitant profit margins) medical treatments that are toxic and deadly, instead of taking two inexpensive (read: minuscule profit margins) drugs that have zero adverse side effects.

It also turns out that Ivermectin is a powerful anti-aging drug!

This is precisely why the war on Ivermectin (and soon Fenbendazole) has only just begun…

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by Dr. Marion Laderoute

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 (ie., 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]. The AFP receptor (AFPr) was expressed on macrophages and highly overexpressed on the common cancers the adenocarcinomas (breast, prostate, lung, colon, etc) implying a dual role in immunosuppression of the host and in tumor malignant potential. In fact I wrote the theory to explain how immunosuppression of the host relates to tumor malignant potential.

Figure 1. From Giannelli G et al, Cancer Research 2014 [4]. AFP is recognized as a malignancy progression factor in a very common cancer in the world, hepatocellular carcinoma (HCC) often associated with a viral origin.

Thus, the malignant potential of tumors known as cancer was amenable to pharmacological intervention.

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 and thus changes were not visible, because AFP binding to the AFPr on tumors blocked incoming signals. So it seemed the tumor did not age.

While the malignant phenotype is now recognized as ‘epithelial-mesenchymal transition’ (EMT), fortunately Dr. Robert Weinberg has also defined it to block senescence [5] or is also a phenotype involving anti-cellular senescence (whew!).

Then in 2015, I wrote the new immunosenescence paradigm of macrophages published in Discovery Medicine which attempts to explain the cause of chronic illness associated with aging including diseases such as cancer and cardiovascular diseases [6]. Subsequently I validated this paradigm specifically for explaining the initiation and progression of cardiovascular diseases [7] (it is not cholesterol but elevated stress does increase cholesterol).

Figure 2. The New Immunosenescence Paradigm of Macrophages

defined as the failed (lytic) release of protector HERV-K102 from foamy macrophages. When the DHEA/cortisol ratio is low, there is a higher risk of immunosenescence when the host encounters a virus due to inadequate levels of DHEA to bind and inactivate AFP. We reported in 1994 that AFP blocks apoptosis of macrophages [8].

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

ZBTB20 is a zinc finger credited with post-natal down-regulation of AFP. However, when functional p53 is absent, it upregulates AFP [9].

Did you know that ZBTB20 is required for the induction of NFKB1 [10] such as when SARS-CoV-2 infects foamy macrophages in vivo by ADE [11]which contributes to cytokine storm? AFP is significantly upregulated by SARS-CoV-2 infection at the protein and mRNA level in cell lines [12].

Referring back to Figure 2, AFP antagonists reverse and prevent immunosenescence. Immunosenescence causes age associated chronic diseases [6,7]. This means AFP antagonists like zinc, flavonoids, DHEA/7ketoDHEA,  Vitamin D over 60 ng/ml, and now also ivermectin [13] are likely AFP antagonists which are 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 [14] and blocking metastasis [15].

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. 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.

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

6. 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. 

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

8. 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.

9. 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.

10. 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.

11. 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.

12. Appelberg S, Gupta S, Svensson Akusjärvi 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. 

13. 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.

14. 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.

15. 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’

Substack by Dr. William Makis MD

Papers reviewed:

• 2023 Sep.23 - Man-Yuan Li et al - Ivermectin induces nonprotective autophagy by downregulating PAK1 and apoptosis in lungadenocarcinoma cells

• 2023 May - Samy et al - Eprinomectin: a derivative of ivermectin suppresses growth and metastatic phenotypes of prostate cancer cells by targeting the β-catenin signaling pathway

• 2022 Nov - Lotfalizadeh et al - The Anticancer potential of Ivermectin: Mechanisms of action and therapeutic implications

• 2022 Oct - Jian Liu et al - Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin

• 2022 Jun - Daeun Lee et al - Ivermectin suppresses pancreaticcancer via mitochondria dysfunction

• 2021 Aug - Shican Zhou et al - Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth

• 2021 Jan - Mingyang Tang et al - Ivermectin, a potential anticancer drug derived from an antiparasitic drug

• 2019 Sep Intuyod et al - Anti-parasitic Drug Ivermectin Exhibits Potent Anticancer Activity Against Gemcitabine-resistant Cholangiocarcinoma In Vitro

• 2018 Feb - Juarez et al - The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug

2018 Feb - Juarez et al - The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug

• Satoshi Omura at the Kitasato Institute discovered Ivermectin in 1979 and was awarded a Nobel Prize in Physiology or Medicine for this discovery in 2015

• Ivermectin was FDA Approved for human use in 1987 to orally treat onchocerciasis, also known as river blindness, caused by the blackfly-transmitted parasite Onchocerca volvulus

• Ivermectin is annually taken by close to 250 million people

• most patients treated with Ivermectin have no side-effects other than those caused by the immune and inflammatory responses against the parasite, such as fever, pruritus, skin rashes and malaise

• maximum concentration in plasma is reached 4-5 h after its oral administration

• its half-life is approximately 19 h and is metabolized in the liver by the cytochrome CYP1A and CYP3A4 complexes, generating 10 metabolites, mostly demethylated and hydroxylated. 

• Its excretion is mainly by feces and only 1% is excreted in the urine

• Ivermectin exerts antitumor effects in different types of cancer.

What this means Clinically:

• Chloride channel - Acute myeloid leukemia - induced cell death

• Akt/mTOR path - glioblastoma, renal cancer cell lines - inhibition of mitochondrial biogenesis or function, oxidative stress, DNA damage

• P2X7 (ICD) overexpression promotes tumor growth and metastases - ivermectin potentiates immunogenic cell death (ICD) in triple negative breast cancer cells

• PAK1 (Autophagy) - glioblastoma and ovarian cancer cell lines - Ivermectin promotes autophagy through this pathway

• WNT-TCF pathway - glioblastoma, colon cancer, melanoma - Ivermectin exerts anti-proliferative function through this pathway (possibilities to use Ivermectin to block WNT-TCF dependent cancers like breast, skin, lung)

• SIN3 Domain - breast cancer (Ivermectin acts as epigenetic modulator to alter gene expression and decrease tumor growth)

• NS3 helicase - glioma cells - Ivermectin had anti-tumor effects by acting as helicase inhibitor

In Vitro Studies:

• breast cancer, ovarian, prostate, colon, pancreas, head and neck, melanoma - inhibits cell proliferation, induction of apoptosis, autophagy, reversion of tamoxifen resistance, inhibits metastases

• glioblastoma - growth inhibition, apoptosis, and anti-angiogenesis

In Vivo Studies (done on immune deficient mice):

• acute myeloblastic leukemia - reduce tumor volume up to 70%

• glioblastoma - reduce tumor volume up to 50%

• breast cancer - reduce tumor volume up to 60%

• glioma - reduce tumor volume up to 50% (at 0.24mg/kg), however at human dose equivalent to 0.8mg/kg tumors were not detectable!

• colon cancer - reduce tumor volume up to 85%

• median dose employed was equivalent to 0.4 mg/kg in humans from 10 to 42 days (oral, intraperitoneal or intra-tumoral)

• the in vitro and in vivo antitumor activities of Ivermectin are achieved at concentrations that can be clinically reachable based on the human pharmacokinetic studies done in healthy and parasited patients

2019 Sep Intuyod et al - Anti-parasitic Drug Ivermectin Exhibits Potent Anticancer Activity Against Gemcitabine-resistant Cholangiocarcinoma In Vitro

• Ivermectin studied on cholangiocarcinoma cells that were chemo resistant (gemcitabine)

• Ivermectin inhibited cancer cell proliferation and colony formation in a dose and time dependent manner(!)

• Ivermectin caused S-phase cell cycle arrest and cell death

• Conclusion: “Ivermectin might be useful as an alternative treatment for cholangiocarcinoma, especially in patients who do not respond to chemo.”

2021 Jan - Mingyang Tang et al - Ivermectin, a potential anticancer drug derived from an antiparasitic drug

• specific mechanism of IVM-mediated cytotoxicity in tumor cells is unclear; it may be related to the effect of IVM on various signaling pathways

• IVM seems to induce mixed cell death in tumor cells

• CONCLUSIONS: Ivermectin selectively inhibits the proliferation of tumors at a dose that is not toxic to normal cells and can reverse the MDR (multi-drug resistance) of tumors.

• In healthy volunteers, the dose was increased to 2 mg/kg, and no serious adverse reactions were found

• Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug

• large number of research results indicate that IVM affects multiple signaling pathways in tumor cells and inhibits proliferation, IVM may cause antitumor activity in tumor cells through specific targets

• Ivermectin regulates the tumor microenvironment, inhibits the activity of tumor stem cells and reduces tumor angiogenesis and tumor metastasis.

• It has become increasingly clear that Ivermectin can induce a mixed cell death mode involving apoptosis, autophagy and pyroptosisdepending on the cell conditions and cancer type. 

• Ivermectin can enhance the sensitivity of chemotherapeutic drugs and reduce the production of resistance. Therefore, IVM should be used in combination with other drugs to achieve the best effect

2022 Jun - Daeun Lee et al - Ivermectin suppresses pancreatic cancer via mitochondria dysfunction

• Poster presentation from South Korea

• Ivermectin was combined with gemcitabine in pancreatic cancer

• Ivermectin-gemcitabine combination inhibited pancreatic cancer cell proliferation via G1 arrest of cell cycle

• in vivo experiments showed ivermectin-gemcitabine significantly suppressed tumor growth of pancreatic cancer compared with gemcitabine alone

• Conclusion: “Ivermectin could be a potential antitumor drug for the treatment of pancreatic cancer”

2021 Aug - Shican Zhou et al - Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth

• Colorectal cancer is 3rd most common cancer worldwide, lacks effective therapy

• Ivermectin tested on colorectal cancer cell lines

• Ivermectin dose-dependently inhibited colorectal cancer growth

  • promoted cell apoptosis

  • promoted total and mitochondrial ROS production (reactive oxygen species)

  • induced colorectal cancer cell S-phase arrest

• Conclusion: Ivermectin might be a new potential anticancer drug therapy for human colorectal cancer

2022 Oct - Jian Liu et al - Progress in Understanding the Molecular Mechanisms Underlying the Antitumor Effects of Ivermectin

• PAK1 (Autophagy) - Ivermectin, acts as PAK1 inhibitor and inhibits growth of breast cancer, ovarian cancer, glioblastoma and NF2tumors and involved in cell death in Nasopharyngeal carcinoma and melanoma.

• Apoptosis (Caspase Dependent) - Ivermectin induces apoptosis in glioblastoma, chronic myeloid leukemia cells, also breast cancer, ovarian cancer.

• Immunogenic Cell Death (ICD - P2X7 signaling) - ivermectin induces cell death in triple negative breast cancer.

• YAP1 Inhibition - hepatocellular and cholangiocarcinoma, colorectal cancer, ovarian cancer, gastric cancer - ivermectin exerts anti-tumor effects

• WNT Path (cancer progression - differentiation, metastasis, cell senescence, tumor initiation, tumor growth) - Ivermectin inhibits this path - inhibits colon cancer and lung cancer, ivermectin also limits formation of cancer stem cells.

• TF3 Path - ivermectin stimulates apoptosis of melanoma cells.

• RNA Helicase Inhibition - ivermectin inhibits cell invasion and proliferation of glioma cells

• SID Peptide (SIN3A/B) - Ivermectin inhibits breast cancer progression, also restores tamoxifen sensitivity

• Akt/mTOR inhibition - Ivermectin inhibits mitochondrial respiration - glioblastoma, CML leukemia (some cancers like breast, leukemia and lymphoma are more metabolically active and depended on mitochondria - more responsive to ivermectin inhibition)

• ivermectin is an angiogenesis inhibitor

• ivermectin has anti-mitotic activity

In humans, toxicity of ivermectin is very low, no serious adverse reactions have been found in healthy volunteers at dose up to 120 mg (~2 mg/kg) (Reference: GuzzoCA, FurtekCI, PorrasAG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122–1133.)

2023 May - Samy et al - Eprinomectin: a derivative of ivermectin suppresses growth and metastatic phenotypes of prostate cancer cells by targeting the β-catenin signaling pathway

• Ivermectin (derivative) inhibits prostate cancer cell viability, migration capacities

• Ivermectin induces apoptosis, autophagy (via ROS)

• Ivermectin downregulates expression of cancer stem cell markers

• Conclusion: Ivermectin has tremendous potential to target metastatic prostate cancer cells and provides new avenues for therapeutic approaches to advanced prostate cancer

2023 Sep.23 - Man-Yuan Li et al - Ivermectin induces nonprotective autophagy by downregulating PAK1 and apoptosis in lung adenocarcinoma cells

• Ivermectin was studied on lung adenocarcinoma cells

• Ivermectin strikingly impeded colony formation and viability of cancer cells, along with cell proliferation, caused apoptosis and enhanced autophagy

• Ivermectin efficiently suppressed cellular growth of lung adenocarcinoma cells in vivo among nude mice’