Off-label Ivermectin attacks cancer in many ways; a Review

Off-label Ivermectin attacks cancer in many ways; a Review

Ivermectin, an antiparasitic drug with very few side-effects, blocks numerous cancer pathways with all manner of cancers, improves drug effectiveness, lowering drug resistance, and appears to have cancer stem cell inhibiting effects.

Ivermectin, or IVM, is an antiparasitic drug, an helminthic, widely used for the treatment of diseases such as scabies, river blindness and elephantiasis. Satoshi Omura (Japan) and William C. Campbell (Ireland) won the 2015 Nobel Prize in Physiology or Medicine for their discovery. 

Originally approved for veterinary use (acariasis, heartworm), it was approved by the FDA for use in humans as long ago as 1978, and has an excellent safety record (1). It is part of the Avermectin family, with few side-effects.

Antiviral effects

IVM also has potential antiviral effects. For example, Australian researchers showed IVM could inhibit the replication of HIV-1 and dengue viruses (2); and a review of research into inhibitors of dangerous flaviviruses (West Nile Virus, Zika Virus, Yellow Fever Virus) by Chinese researchers concluded that no new antiviral drug had truly been successful but that all these viruses had a dependency on the helix lysis function of NS3 helicase and Ivermectin was proven to block this (3). For example, IVM was proven to be an inhibitor of Yellow Fever Virus (4)

Researchers have also noted a ‘multiobjective behaviour’ in Ivermectin, through its homologs, which can inhibit Covid-19 (5).

Ivermectin and cancer

Ivermectin has significant anticancer effects (1). From various studies, a number of which can be found here, these include:

  • Anti-angiogenic - blocking development of blood supplies
  • Inhibits proliferation and metastasis
  • Regulates multiple signalling pathways through AMPK and PAK-1 kinase
  • Induces programmed cell death, apoptosis and autophagy
  • Inhibits cancer stem cells
  • Boosts immune system
  • Reverses drug resistance across many drugs

IVM really does appear to target a multitude of pathways. For example, the AMPK pathway and the PAK1 pathway, each of which has a number of pathways with which they cross-talk. In other words, controlling these can control many others. For example, PAK1 lies at the crossroads of many paths key to tumour formation, growth, proliferation and metastasis. When highly activated, cancer is more aggressive. PAK1 inhibitors are being developed but to date, IVM seems more effective, works on more cancers and with less side-effects.

HSP27 is another such ‘controller’ pathway that Ivermectin also targets. Subsidiary pathways targeted by Ivermectin include mTOR, Akt, YAP1 and Wnt/β-catenin. Other targets include SIN3, TFE3, KPNB1, and it inhibits MDR protein and p-glycoprotein, activates chloride channels in leukaemia, increases TFE3 in melanoma and inhibits DDX23 helicase in GBM.

IVM also inhibits cancer in many ways at doses that are non-toxic to healthy cells.

Although a great deal of the research has been in vitro, rather than in vivo, it has been concluded that the optimal usage of Ivermectin seems to be at the same time as chemotherapy.

Breast cancer, TNBC and Ivermectin

There is research showing that IVM can target PAK1 in breast cancer (9). It also preferentially targets breast cancer stem cells in tumours over other cancer cells, also inhibiting other cancer recurrence-stimulating factors, mainly through the PAKi-STAT3 axis which regulates IL-6. City of Hope researchers showed that that P2X7 receptor presence correlated with the ability of breast cancer to grow;ivermectin could attack this pathway causing apoptosis.  Ivermectin also released ATP and HMGB1, key mediators of inflammation and could thus boost the immune system preventing further cancer growth. This research took place with both breast cancer and Triple Negative Breast Cancer (9).

A team from the University of Geneva showed that IVM could block the Wnt-TCF pathway. This is hugely important because it means that Ivermectin can attack and destroy cancer stem cells (9) and this has been shown in breast cancer and lymphoma.

It also has specific research with TNBC, where it seems to reawaken protective pathways, actually making TNBC cells ‘blockable’ by Tamoxifen. Ivermectin has strong epigenetic benefits, helping to correct issues in the microenvironment of the cell. Its activities were found not to be solely cytotoxic, but it regulated the cancer cell microenvironment and, for example, promoted an immune response.

Prostate cancer and Ivermectin

IVM has been shown to inhibit prostate cancer cells, enhance the performance of Enzalutamide; and reduce drug resistance with Docetaxel.

Ivermection reduces drug resistance

Apart from the above work with Docetaxel (adriamycin), Chinese researchers in Beijing showed that Ivermectin could counter drug resistance in solid timours and leukaemia in vivo. Other studies showed effect with tacol (9)

Lung cancer and Ivermectin

IVM was shown to significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity as for gastric cancer below (6) IVM also combined with erlotinib to produce a stronger cancer cell killing effect by regulating EGFR activity. IVM also reduced the metastasis of lung cancer cells by inhibiting EMT.

Ovarian cancer and Ivermectin

Dr Hisashi Hashimto showed that Ivermectin could block the PAK1 pathway in ovarian cancer in 2009 (9). 2020 research from Chinese scients show Ivermectin can block a number of pathways in Ovarian cancer cells (10).

Gastric, liver cancer and Ivermectin

A 2017 study showed that IVM could inhibit gastric cancer in vivo as well as in vitro (6). This was better the more the cancer depended upon the YAP1 pathway. This same effect was found in Liver cancer (7).

Colorectal cancer and Ivermectin

A 2021 study showed that IVM could inhibit Colorectal cancer cells dose-dependently, increasing Caspase-3/7 activity and causing cell apoptosis. IVM promoted both total and mitochondrial ROS production in a dose-dependent manner, so Ivermectin probably should not be used with antioxidants or off-label drugs such as NAC (8).

Overall

To repeat, there are no clinical trials and only a little in vivo work.

IVM seems to attack many pathways including important ‘controller’ pathways.

It seems to improve drug performance and restrict drug resistance.

It has very few side-effects.

If this is shown in real life, Ivermectin could be a significant upgrade on other anti-helminthics such as Fenbendazole and Mebendazole. We shall see.

Go to: Fenbendazole and cancer

 

*****

References

 

  1. Ivermectin, a potential anticancer drug derived from an antiparasitic drug;  Mingyang Tang, Xiaodong Hu et al; Pharmacol Res; 2021 Jan; 163: 105207; 

  2. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus; Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. Biochem J. 2012;443(3):851–856

  3. Flavivirus: From Structure to Therapeutics Development; Rong Zhao, Meiyue Wang, Jing Cao,  Jing Shen, Xin Zhou, Deping Wang, and Jimin Cao; Life (Basel) 2021 Jul; 11(7): 615.

  4. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug; Mastrangelo E., Pezzullo M., De Burghgraeve T., Kaptein S., Pastorino B., Dallmeier K., de Lamballerie X., Neyts J., Hanson A.M., Frick D.N., Bolognesi M., Milani M.  J Antimicrob Chemother. 2012;67(8):1884–1894. 

  5. Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach; Lenin González-Paz, María Laura Hurtado-León, et al;  Biophys Chem; 2021 Nov; 278: 106677.

  6. Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer; Nambara S., Masuda T et al; Oncotarget. 2017;8(64):107666–107677.

  7. Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice; Nishio M., Sugimachi K.et al; Proc Natl Acad Sci 2016;113(1):71–80.

  8. Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth; Shican Zhou, Hang Wu et al; Front Pharmacol, 2021 Aug 13;12:717529 

  9. Parasite Killer Ivermectin stops cancer drug resistance

  10. Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes; EPMA Journal; 2020 May 28;11(2):289-309.

 


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2022 Research
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