Ivermectin - antiparasitic drug's anticancer potential

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Description of the potential effects of the substance Ivermectin based on the literature. (This is not a product description, disclaimer at the bottom of the page)

 

Table of contents

1. Ivermectin: Discovering the anticancer potential of an antiparasitic drug. 1
2. Introduction. 3
3. Ivermectin – the birth of a powerhouse in medicine. 3
4. Mechanism of action: how does ivermectin work?. 4
5. Mechanisms of antitumor action of ivermectin. 5
6. Induction of apoptosis and cell cycle arrest. 5
7. Inhibition of key cancer signaling pathways.. 6
8. Modulation of the tumor microenvironment. 6
9. Endoplasmic reticulum stress and apoptosis. 7
10. Mitochondrial dysfunction and cancer cell death. 7
11. Modulation of autophagy 7
12. Possible cancer treatment protocols with ivermectin. 8
13. Preclinical and clinical evidence. 8
14. Breast cancer: 8
15. Triple-negative breast cancer (TNBC) 9
16. Regulation of the tumor microenvironment. 10
17. Stomach cancer. 10
18. Tumors of the liver and biliary tract. 11
19. Renal cell carcinoma (RCC) 11
20. Prostate cancer. 12
21. Leukemia. 13
22. Cervical cancer. 14
23. Ovarian cancer. 14
24. Brain glioma. 15
25. Lung cancer. 16
26. Pancreatic cancer: 17
27. Bladder cancer: 17
28. Head and neck cancer: 17
29. Esophageal cancer: 18
30. Drug delivery and formulation. 18
31. Nanoparticle-based drug delivery. 18
32. Liposomal Ivermectin. 19
33. Connection to drug carriers.. 19
34. Cancer stem cells and immunity. 19
35. The role of ivermectin in targeting cancer stem cells (CSCs) 19
36. Multidrug resistance (MDR) reversal: 20
37. Ivermectin and the immune system. 20
38. Synergy with immune therapies: 20
39. Effects on tumor-associated macrophages (TAM) 20
40. Comparative analysis. 21
41. Ivermectin vs. other reformulated drugs. 21
42. Side effects and toxicity profiles 21
43. Clinical research roadblocks and future research challenges. 22
44. Potential biomarkers of ivermectin sensitivity. 22
45. Preclinical (animal) vs. clinical (human) studies 22
46. Combination therapies: Ivermectin with conventional cancer treatments. 23
47. Increasing the effectiveness of chemotherapy: 23
48. Improving immunotherapy outcomes: 23
49. Overcome multidrug resistance: 24
50. Reducing tumor stemness: 24
51. Clinical trials and future prospects. 24
52. Phase II study in glioblastoma multiforme: 25
53. Breast cancer research: 25
54. Colorectal cancer research: 25
55. Other potential research: 25
56. Conclusions: The way forward for ivermectin in oncology 26
57. References: 26

 

Introduction

Ivermectin, since its discovery and development in the 1970s through the research of two scientists—Japanese microbiologist Satoshi Omura and Irish parasitologist William C. Campbell, has evolved wonderfully over time. (1)
This is a „miracle” drug in the true sense of the word, provided it has the potential to fight many diseases, infections, and even fatal conditions such as cancer.
As research continues into the various possible mechanisms of action of Ivermectin, discoveries continue to take place and newer uses of Ivermectin are being introduced into clinical practice. (2)
In summary, since its development as a potent antiparasitic drug for the treatment of parasites, Ivermectin has achieved a transformation of millions through parasitic disease elimination activities, mainly in developing regions of the world. Modern research shows that Ivermectin has the potential to act as a drug against several inflammatory diseases and viral infections, prompting scientists to explore its potential for many medical applications. (3)

Ivermectin – the birth of a powerhouse in medicine

The medical industry first recognized ivermectin as an antiparasitic drug through Merck Sharp & Dohme (MSD) in 1981 after the substance was discovered in the soil bacteria Streptomyces avermitilis. (4)
After making this discovery, scientists and researchers began conducting tests on humans, observing how well Ivermectin treats parasitic infections in animals, thanks to its effectiveness in eliminating the infectious process from the infected host. (5)
In the late 1980s, health authorities recommended the use of ivermectin to treat onchocerciasis (river blindness), which has affected many people in Africa and South America. (6)
Thus, what began merely as an anti-parasitic drug has now become a widely used treatment for several diseases and infections, the most common of which include:

• Strongyloidiasis – parasitic intestinal infection
• Scabies – it is characterized by an infestation of mites that spread rapidly among people.
• Lymphatic filariasis – a parasitic disease transmitted by mosquitoes
• Head lice – as an alternative to conventional treatment methods

Ivermectin has become a global public health tool through mass drug administration programs that have reduced the impact of parasitic diseases around the world. This is indeed a very big milestone for the drug. (7)
Since its discovery, Ivermectin has gained widespread public recognition during the COVID-19 pandemic, while maintaining its original role as an important life-saving antiparasitic drug. (8)
The combined research of Dr. Satoshi Ōmura and Dr. William C. Campbell helped discover ivermectin as a treatment for human and animal parasites, which later led to a Nobel Prize for them in 2015. (9)

Mechanism of action: how does Ivermectin work?

Ivermectin mainly acts on the nervous system of the parasite that has infested the animal or human host. Once inside the body, Ivermectin binds to the parasite's nervous system to eliminate it. (10)
The drug attaches to glutamate-gated chloride channels, triggering the movement of chloride ions, which causes paralysis of the parasite and its eventual death. (11) Lacking the same channels in human cells, Ivermectin is safe for patients when taken as prescribed by a physician. However, prolonged exposure to high doses of ivermectin can also adversely affect nervous system receptors in ways that can cause neurotoxic effects in the affected individual. (12)
Similarly, in the world of veterinary medicine, certain dog breeds, such as Australian Shepherds and collie, require special attention when prescribing ivermectin. The reason for this is the lack of protective P-glycoprotein in these particular dog breeds. (13)
Deficiency of this protein makes these dogs susceptible to developing neurotoxicity to Ivermectin, which can lead to harmful consequences such as ataxia, tremors and even coma. (14) Therefore, caution should be exercised before prescribing ivermectin to humans and animals with special conditions or deficiencies, in addition to those mentioned above.
Different biological structures and receptors among organisms cause Ivermectin to affect them in different ways. The drug acts on glutamate-gated chloride channels in worms and lice, as these channels sustain both nerve and muscle activity. (13) Chloride permeability increases when the drug attaches to glutamate-gated chloride channels and causes paralysis, which leads to the death of the parasite.
The absence of these chloride channels in human biology makes the drug safe during permitted use scenarios. Reduced activity of the P-glycoprotein, which regulates the removal of the drug in dogs, leads to their neurological toxicity whenever they encounter Ivermectin. The drug acts differently on different species because it targets parasites, but causes limited risk to humans and limited effects on some dogs with genetic susceptibility. (14)

Mechanisms of antitumor action of ivermectin

Some of the widely accepted hypotheses and theories regarding the anticancer effects of ivermectin are discussed below:

Induction of apoptosis and cell cycle arrest

Scientific studies show that ivermectin activates programmed cell death (apoptosis) in various types of cancer cells. (15)
A study by the Anticancer Research Journal found that ivermectin activates apoptosis mechanisms in cancerous colon and breast tissues through the following sequence (16):

• The expression level of proapoptotic proteins, such as Bax, becomes higher with ivermectin treatment.
• Reduction in anti-apoptotic proteins such as Bcl-2
• These enzymes activate caspase, which leads to cell destruction.
• Cancer cells stop dividing after ivermectin administration, as the drug stops cell cycle progression in G1 and G2/M phases and blocks tumor growth.

In summary, some medical therapies, along with interventions, have significant effects on cellular processes that cause cells to change their function. Cell death by apoptosis occurs because Bax expression increases, while Bcl-2 decreases and caspases become active. (16)
Through molecular events, the cell experiences a controlled disassembly process that removes damaged or unwanted cells from the body. The cell cycle can be stopped in the G1 phase or in the G2/M phase due to cell cycle arrest.
Cell cycle progression stops when a cell is arrested in this phase during DNA repair or when proliferation of potentially dangerous cells is halted. Cellular integrity along with avoidance of abnormal cell growth depends on the coordinated actions of apoptosis and cell cycle arrest as critical mechanisms. (15)

Inhibition of key cancer signaling pathways

Many signaling pathways are seen as driving forces behind cancer development and its subsequent progression. (17)
Studies show that ivermectin effectively stops cancer signaling pathways, resulting in reduced tumor growth and expansion and a reduced risk of metastasis. (17)
Signal transduction networks function as essential elements in cancer development, as each network controls important cellular processes. Tumor growth and invasion take place through the WNT/β-catenin pathway, in which β-catenin activation leads to the expression of genes that drive cancer cell proliferation and metastasis.
The process of β-catenin activation is inhibited by ivermectin treatment, which limits the growth and spread of cancer cells. Survival and resistance to programmed cell death and enhancement of cancer cell growth depend on the PI3K/Akt/mTOR signaling pathway. (17)
The drug Ivermectin interrupts these mechanisms of cancer cell survival and simultaneously induces cell death through apoptosis. The NF-κB signaling pathway regulates inflammation along with metastasis, as these processes are crucial to the spread and progression of cancer. (17)
By reducing inflammation, ivermectin shows the potential to prevent the metastasis of cancer cells, thereby stopping the spread of cancer. Ivermectin shows therapeutic potential in treating cancer by affecting major cell signaling pathways, enabling stronger cancer cell death.

Modulation of the tumor microenvironment

The tumor microenvironment (TME) plays an important role in cancer resistance to therapies. Studies have shown that ivermectin has the ability to alter the tumor environment, thereby improving their response to cancer treatment. (18)
According to the research, the following findings were noted:

• The immune response becomes more effective against cancer because ivermectin eliminates cells that inhibit immune function. (19)
• An interesting aspect of ivermectin is that it helps change tumors from a low immune (cold) state to a high immune (hot) state, which energizes and enhances the impact of immunotherapeutic processes. (20)

Endoplasmic reticulum stress and apoptosis

Laboratory studies have shown that ivermectin induces endoplasmic reticulum (ER) stress in cancer cells, thereby triggering an unfolded protein response (UPR).
Biological stress imposed on the endoplasmic reticulum both impairs protein handling and activates cell suicide mechanisms that lead to fatal consequences for cancer cells.
Studies show that Ivermectin enhances processes through the ER stress markers CHOP and ATF4 to induce cancer cell death. The ER stress response pathway makes Ivermectin a promising therapeutic approach against cancers that have developed drug resistance.

Mitochondrial dysfunction and cancer cell death

Mitochondria play a key role in the metabolism and survival of cancer cells. Ivermectin disrupts mitochondrial function by inhibiting oxidative phosphorylation and promoting the accumulation of reactive oxygen species (ROS).
This leads to depolarization of the mitochondrial membrane, release of cytochrome c and activation of caspases, ultimately resulting in apoptosis.
In addition, ivermectin has been shown to downregulate mitochondrial fusion proteins, impairing the adaptive responses of cancer cells to metabolic stress. These findings underscore its potential as a metabolic disruptor in oncology.

Modulation of autophagy

Autophagy is a cellular process that cancer cells use to survive under stressful conditions, including chemotherapy and nutrient deprivation. Ivermectin has been found to modulate autophagy by inhibiting autophagosome formation and promoting autophagic cell death.
In preclinical studies, ivermectin reduced levels of autophagy-related proteins such as Beclin-1 and LC3-II, sensitizing cancer cells to chemotherapy. This dual action of inhibiting survival autophagy while promoting cytotoxic autophagy makes ivermectin a promising candidate for combination therapies in cancer treatment.
These expanded sections add depth to the existing content, including additional cancer types, drug delivery strategies and mechanistic insights into the anticancer potential of Ivermectin.

Possible cancer treatment protocols with ivermectin

Although ivermectin has no officially recognized cancer treatment protocols, several alternative medicine practitioners have investigated its potential therapeutic value.

• Several doctors, along with research experts, believe that administering 12 mg of ivermectin twice a day shows potential benefits in cancer treatment. These anecdotal reports of ivermectin use have no proven benefit in large clinical trials. (21)
• Several physicians in Poland have used Ivermectin along with Fenbendazol and THC (tetrahydrocannabinol) in the combination treatment of certain cancers, according to anecdotal observations. However, more studies are needed to verify both the efficacy and therapeutic properties of Ivermectin. (22) (23)
• Some hypotheses indicate that Ivermectin has the ability to improve the efficacy of traditional chemotherapy or immunotherapy when used as part of their combination treatment. In order to develop official protocols for the use of ivermectin in cancer therapy, further research needs to be conducted along with clinical trials. (16)

 

Preclinical and clinical evidence

Various experiments in laboratory conditions and on animals have shown that Ivermectin exhibits anticancer properties. (16)
Since listing all of them may be beyond the scope of this article, it is better to review the anticancer role of ivermectin in some of the world's most common cancers.

Breast cancer:

Breast cancer is one of the most common types of cancer found worldwide. It develops from mutated breast epithelial cells that arise from several carcinogens. (24)
Breast cancer is one of the most common malignancies among women worldwide, and statistics show that a new diagnosis is made every eighteen seconds. (24)
The development of breast cancer depends on genetic susceptibility, hormonal problems, lifestyle habits and exposure to toxins in the environment.
Conventional therapies including surgery combined with chemotherapy and radiation and targeted therapies are encountering drug resistance, and patients are experiencing relapses. (25)
Ivermectin produces specific effects that favorably control cell growth and proliferation in various cell lines. Laboratory experiments have shown that ivermectin reduces cell proliferation in human breast cancer cell lines MCF-7, MDA-MB-231 and MCF-10.
By inhibiting the Akt/mTOR pathway, ivermectin blocks a fundamental cellular mechanism necessary for cell growth and survival. Through autophagy, ivermectin promotes the breakdown of cellular material and leads to tumor destruction. Through its mechanism of action, ivermectin specifically inhibits the activity of the PAK1 protein, which supports its anti-tumor effect on cell proliferation. (26)
Ivermectin exhibits antiproliferative activity and does not cause apoptotic activation in canine CMT7364 and CIPp cells. Through its ability to block cell cycle progression, it prevents at critical stages and simultaneously blocks the Wnt signaling pathway, which contributes to tumor growth and metastasis.
Through these mechanisms, ivermectin is showing its potential as a versatile therapeutic agent in both human and animal models of cancer.

Triple-negative breast cancer (TNBC)

TNBC shows extreme aggressiveness because the disease lacks detectable estrogen receptors combined with the absence of progesterone receptors and HER2 protein. (27)
Ivermectin shows promise in treating this type of cancer:

• It mimics SID functions by blocking the connection between SID and α-helix 2.
• The mechanism manipulates the EMT E-cadherin gene to reactivate tamoxifen sensitivity in triple-negative breast cancer cases.
• It works by controlling a drug-resistant type of breast cancer stem cell that stimulates tumor growth and disease recurrence. (28)

 

Regulation of the tumor microenvironment

Ivermectin affects the tumor microenvironment in breast cancer patients in the following ways:

• High ATP levels promote greater HMGB1 release through P2 × 4/P2 × 7/Pannexin-1 channels. (29)
• This substance activates immunogenic death processes mediated by the immune system, along with inflammatory reactions.
• TAMs undergo modulations as a result of therapy, resulting in a change in their phenotype from M2 to the anti-tumor subtype M1.

Stomach cancer

Gastric cancer is the third deadliest cancer in the world, causing deaths due to its existence and subsequent complications. (30)
Ivermectin exhibits tumor cell inhibitory activity in gastric cells in both laboratory studies and in living organisms of the YAP1 protein, by targeting, thereby enhancing the therapeutic response of MKN1 and SH-10-TC cells expressing YAP1. (31) (32) The drug therefore prevents angiogenesis and blocks the action of important cancer-promoting cytokines.
Studies show that Ivermectin exhibits both inhibition of cell proliferation and increased apoptosis in CC14, CC36, DLD1 and Ls174T cells. The Wnt signaling pathway is blocked by ivermectin, which normally functions to promote tumor growth and survival.
The cycle of cancer cell proliferation is disrupted by Ivermectin treatment, which promotes cancer cell death. (16) The administration of ivermectin in cells leads to increased expression levels of caspase-3, which is involved in apoptotic cell death.
The two mechanisms of Wnt pathway inhibition, along with increased caspase-3 expression, act as a double-edged approach that terminates tumor expansion and activates programmed cell death, thereby positioning Ivermectin as a strong candidate for preventing cancer cell survival. (33)

• Ivermectin targets cancer stem cells (CSCs) to reduce the risk of cancer recurrence and treatment failure.
• The mechanism for preventing metastasis depends on stopping the epithelial-mesenchymal transition (EMT).
• Ivermectin helps increase the efficacy of 5-FU in combination with oxaliplatin, helping to achieve better results when used as standard therapy. (34)

Tumors of the liver and biliary tract

The bile ducts, along with the liver, are aggressive malignant tissue that attacks these organs, including the bile ducts and gallbladder. (35) These cancers become difficult to detect in the early stages because they do not produce any detectable signals until they reach the later stages of development.
The most common type of primary liver cancer is hepatocellular carcinoma (HCC), which develops mainly in people with chronic liver disease and hepatitis infections and cirrhosis. (36)
Diagnosis of biliary tract cancer along with gallbladder cancer remains highly lethal, as patients develop symptoms too late and treatment options are limited.
Many factors contribute to the development of liver cancer, including obesity, alcohol consumption and hereditary tendencies.
New therapies need attention, and screening for early detection is becoming essential, as improvements in treatment have not led to improved patient survival outcomes. (37)

• The development of hepatocellular carcinoma in Mob1b-/- mice is stopped because YAP1 activity is blocked by the drug.
• Studies indicate that ivermectin blocks KKU214 cell proliferation and arrests the cell cycle in S phase, while inducing gemcitabine-resistant cell death.
• Reducing tumor progression through fibrosis helps protect against the negative effects of cirrhosis on tumor formation.

Renal cell carcinoma (RCC)

Renal tubules are the source of renal cell carcinoma, which remains the most common form of kidney cancer. The disease progresses without noticeable symptoms before symptoms such as urine bleeding and pain in the side along with unexpected weight loss appear. (38)
Risk factors for developing renal cell carcinoma are smoking and obesity, as well as high blood pressure and family history combined with heredity.
Since RCC shows resistance to traditional chemotherapy, surgery is the main treatment option for localized cases of renal cell carcinoma. Targeted therapies along with immunotherapy options become essential when advanced stages of the disease are present. (39)
People who are diagnosed with RCC in a timely manner have better survival outcomes, as late-stage RCC shows worse prognostic factors.
Aggressive renal cell carcinoma remains resistant to standard treatments.
However, even in this case, ivermectin causes specific inhibition of RCC cell lines, allowing normal kidney cells to remain intact:

• Inducing mitochondrial dysfunction.
• Reduction in ATP production.
• Increased expression of HEL (mitochondrial stress marker).
• Combining tyrosine kinase inhibitors with ivermectin treatment improves treatment efficacy.

Prostate cancer

The most common form of cancer in men develops gradually inside the prostate gland, remaining asymptomatic until the later stages of the disease. (40)
Most cases of prostate cancer develop without noticeable symptoms for a long time before late-stage symptoms appear, such as difficulty urinating and the presence of blood in the urine and pelvic discomfort. (41)
Older age, hereditary predisposition and improper hormone levels are the main risk factors for this condition.
Prostate cancer is on the spectrum of aggressiveness, as many patients reveal such slow-growing tumors that active surveillance proves to be the most appropriate course of action.
The exact treatment depends on the stage of the cancer, although surgical interventions along with hormonal radiation therapy and patients at an advanced stage may require chemotherapy.
People who undergo PSA testing and digital rectal examination before the onset of symptoms increase their chances of early treatment for prostate cancer.
Expression of the AR-V7 variant responsible for CRPC's drug resistance decreases as a result of this treatment. Studies show that Ivermectin exhibits both inhibition of cell proliferation and increased apoptosis in CC14, CC36, DLD1 and Ls174T cells. (42) The Wnt signaling pathway is blocked by ivermectin, which normally functions to promote tumor growth and survival.
The proliferation cycle of cancer cells is disrupted by Ivermectin treatment, which promotes cancer cell death. Ivermectin administration in cells leads to increased expression levels of caspase-3, which is involved in apoptotic cell death.
The two mechanisms of Wnt pathway inhibition, along with increased caspase-3 expression, act as a double-edged approach that terminates tumor expansion and activates programmed cell death, thereby positioning Ivermectin as a strong candidate for preventing cancer cell survival.

Leukemia

Leukemia manifests itself as a cancer that attacks both the blood and bone marrow through abnormal processes of producing white blood cells.
Leukemia prevents the body from defending itself against infection while producing blood cells and controlling bleeding. There are several types of leukemia, with acute and chronic versions of lymphocytic and myeloid leukemia as distinct subtypes. (43)
Symptoms of leukemia include fatigue, exhaustion combined with the constant progression of the disease and sensitive skin and unexpected weight loss. People contract the disease due to genetic abnormalities combined with exposure to chemicals or radiation, as well as specific viral infections.
Various cancer treatments include chemotherapy along with targeted therapy and bone marrow transplants, depending on the stage of leukemia and its type. Successful treatment results become more feasible when the disease is diagnosed at an early stage.

• Ivermectin shows high specificity against leukemic cells, while maintaining a low level of toxicity to host cells.
• This action increases the amount of chloride ions inside the cells, while making the plasma membrane more negatively charged.
• Ivermectin also triggers ROS production, increasing apoptosis. It also works synergistically with cytarabine and daunorubicin and helps enhance their effects. (44)
• The treatment effectively stops tumor expansion in K562 cells that have chronic myeloid leukemia.
• Treating the tumor microenvironment with the drug improves the immune system's ability to recognize it.

Cervical cancer

Cervical cancer forms inside the cervix, where high-risk strains of human papillomavirus (HPV) remain active as the main cause of the condition. (45)
This cancer develops gradually, starting with precancerous lesions that can be detected by regular PAP smears.
Cervical cancer in its early stages usually produces no symptoms, while the advanced form of this disease causes vaginal bleeding and pelvic pain and discomfort during sexual intercourse. (46)
HPV vaccination, combined with regular screening and prompt treatment of precancerous lesions, is effective in reducing the likelihood of developing cervical cancer. Surgery along with radiation and chemotherapy are treatment options for patients depending on the stage of the disease.
Studies indicate that ivermectin shows significant potential in treating cervical cancer cells that use HeLa as their lineage. (47)
The substance blocks cell reproduction while stimulating programmed cell death, which together generate effective tumor cell suppression. Ivermectin's life-cycle blocking mechanism blocks the progression of the G1/S phase, resulting in the activation of the apoptotic pathway.
The treatment process also inhibits the expression of the E6 and E7 oncogenes, as these genes promote the survival of cervical cancer cells. Studies show that ivermectin has therapeutic value in treating cervical cancer because it works through these important cellular pathways.

Ovarian cancer

Ovarian cancer is classified as a silent killer because it remains hidden until it spreads to other parts of the body.(48)
Symptoms of bloating, abdominal pain and appetite changes tend to be vague, which can lead people to misdiagnose them as other medical issues.
People with BRCA1 or BRCA2 genetic mutations along with hereditary cancer risk and hormonal influences are more susceptible to ovarian cancer. (49)
There is no screening method available for early detection of ovarian cancer, so genetic counseling and prevention strategies become important for those at high risk.
Patients with advanced brain cancer receive combination treatment, which combines surgical removal with chemotherapy, but are increasingly benefiting from targeted medicine. Survival outcomes become much better when cancer patients are detected early at the right stage.

• Inhibits proliferation by inhibiting PAK1 kinase.
• Induces apoptosis through KPNB1-dependent pathways.
• The combined effect of ivermectin with paclitaxel and cisplatin leads to better treatment outcomes.
• Through its mechanism, ivermectin targets cancer stem cells, reducing the risk of recurrence of the disease

Brain glioma

Gliomas develop within the glial cells of brain tissue, which provide support for nerve cells. Different types of brain tumors vary widely in their development, with slow-growing, low-grade gliomas being the opposite of dangerous gliomas, which are the most deadly subtype. (50)
Symptoms of a brain tumor depend on how far the cancer has spread and where it is located, and can manifest as headaches, as well as seizures and cognitive and neurological disorders such as weakness or loss of vision.
Scientists are still unclear about the causes of brain glioma, but heredity and radiation appear to play a role in its formation.
Gliomas pose a challenge for medical intervention due to their rapid multiplication and resistance to therapeutic approaches, including surgery, radiation and chemotherapy. Scientists continue to conduct research to develop new therapeutic approaches, such as immunotherapy, to increase patient survival rates. (51)
Research statistics indicate that the survival rate for glioma patients is 14 to 17 months until death.
Temozolomide, along with surgery and radiation therapy, is the standard treatment for this type of cancer, although resistance is a major challenge. Ivermectin shows potential through:

• Induction of apoptosis in U87 and T98G cells.
• The Akt/mTOR pathway serves as a treatment target in U251 and C6 glioma cell studies. (52)
• The cellular process of brain microvascular endothelial cells leads to inhibition of tumor angiogenesis by triggering apoptosis.
• The permeability of the blood-brain barrier (BBB) increases under ivermectin treatment, which increases the delivery of the drug across the barrier.

 

RNA helicase inhibition

DDX23 helicase activity appears to be blocked by ivermectin, which inhibits miR-21 function in gliomas, thereby targeting tumor cell growth and proliferation properties. Moreover, Ivermectin also attacks glioma stem cells, as they play a role in treatment resistance. (53)

Lung cancer

Studies show that lung cancer consists of two main types, which are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among the most deadly and aggressive cancers in the world. (54)
Studies indicate that Ivermectin exhibits anti-tumor properties in lung cancer cells by activating cell death mechanisms and blocking cell growth, as well as blocking harmful signaling networks. [55]
Ivermectin exhibits anti-NSCLC properties by inhibiting an important Wnt/β-catenin signaling pathway that promotes the evolution of lung cancers. Studies have shown that ivermectin both disrupts mitochondrial function and provokes the production of reactive oxygen species, resulting in elevated rates of apoptosis in SCLC models.
Studies have shown that ivermectin works synergistically with the chemotherapeutic drugs cisplatin and paclitaxel to reduce tumor growth and improve survival statistics.

Pancreatic cancer

Malignant pancreatic cancer is one of the most deadly cancers due to its aggressive behavior and poor response to standard medical interventions. [56]
Numerous scientific reports show that ivermectin shows promise as an additional therapy for pancreatic cancer because it makes cancer cells respond better to chemotherapy. [57]
Preclinical studies of ivermectin show that the drug blocks pancreatic tumor growth by interfering with glucose metabolism in cells and reducing the glycolytic processes that cancer cells need to survive.
Numerous reports indicate that ivermectin is effective against pancreatic cancer stem cells, in addition to its role in improving the efficacy of standard treatment.
Laboratory results indicate that pancreatic cancer patients who receive gemcitabine chemotherapy along with ivermectin experience increased tumor apoptosis along with reduced pathological indices in xenograft models.

Bladder cancer

The antitumor properties of ivermectin are promising for the treatment of urothelial carcinoma, which falls under the category of bladder cancer. (58)
Studies show that Ivermectin blocks survival pathways, including the PI3K/Akt/mTOR signaling cascade, which drives bladder cancer growth. (59)
Studies show that ivermectin has the ability to block the epithelial-mesenchymal transition (EMT), which promotes the metastasis of bladder cancer cells and the development of chemo-resistance.
Studies conducted to date suggest that Ivermectin enhances Bacillus Calmette-Guerin (BCG) treatment to kill cancer cells in patients with non-invasive bladder cancer. Additional clinical evaluations and human validation tests need to be conducted to prove the efficacy of this drug in a medical setting.

Head and neck cancer

Malignancies occurring in the tissues of the head and neck, which include squamous cell carcinoma of the oral cavity along with the larynx and pharynx, are a difficult group because they show rapid growth and frequent recurrence. (60)
Scientific evidence suggests that ivermectin shows therapeutic potential in head and neck cancers by slowing cell growth and causing tumor death, as well as blocking the growth of blood vessels.
Studies have shown that ivermectin reduces epidermal growth factor receptor (EGFR) activity in head and neck squamous cell carcinoma (HNSCC), as the receptor is usually overexpressed in HNSCC.
Ivermectin makes tumor cells more sensitive to radiotherapy while adjusting their DNA damage response networks. Studies call for analyzing its efficacy as a radiosensitizing therapy in patients with squamous cell carcinoma of the head and neck.

Esophageal cancer

Survival rates for patients with esophageal cancer remain drastically unfavorable, along with poor diagnosis at detectable stages.
Laboratory studies have shown the usefulness of ivermectin in the treatment of esophageal cancer, as it prevents cell expansion while increasing programmed tumor cell death.
Cancer cell death increases when Ivermectin activates a dual mechanism that affects oxidative stress and mitochondrial dysfunction in cells. Recent studies indicate that Ivermectin causes esophageal tumors to reduce markers of cancer stem cells, thereby minimizing tumor recurrence. (61)
Clinical trials are currently underway to combine ivermectin with fluoropyrimidines and platinum-based compounds as standard cancer treatments.

Drug delivery and formulation

Nanoparticle-based drug delivery

The availability of ivermectin for cancer treatment is improving as researchers develop advanced drug delivery platforms using liposomal and nanoparticle formulations.
Ivermectin achieves enhanced delivery to tumor sites, as well as prolonged circulation time and improved solubility due to nanoparticle health systems.
Current studies show that nanotechnology-based ivermectin formulations enable better uptake of the drug by cancer cells and minimize unintended consequences.
The administration of ivermectin through these precise methods works to increase both the effectiveness of the treatment and minimize unwanted side effects throughout the body.

Liposomal Ivermectin

Scientists have developed liposomal versions of ivermectin to achieve both pharmacological enhancement and more potent anti-cancer effects. (62)
Protection of the drug by liposomal encapsulation results in both a longer half-life and increased accumulation of the drug in tumor tissue.
Current laboratory studies show that liposomal Ivermectin protects normal tissues from harmful effects because it induces apoptosis of cancer cells.

Connection to drug carriers

The use of polymer micelles and dendrimers serve as carriers for ivermectin to ensure controlled delivery of the drug and better therapeutic outcomes for cancer patients.
Drug delivery systems improve ivermectin's ability to treat cancer by eliminating the drug's solubility obstacles and increasing therapeutic efficacy.

Cancer stem cells and immunity

The role of ivermectin in targeting cancer stem cells (CSCs)

The anticancer properties of ivermectin turn it into an effective therapy against cancer stem cells (CSCs).
Cancer recovery is achieved through specialized cells known as cancer stem cells (CSCs), which are responsible for creating new tumors along with their ability to spread and survive various treatments.
Cancer stem cells are a major obstacle for oncology because they have unlimited reproductive potential and are resistant to traditional cancer treatments. (63)
Ivermectin destroys cancer stem cells through its ability to block Wnt/β-catenin and Hedgehog signaling mechanisms that sustain the presence and proliferation of CSCs.
Treatment efficacy is enhanced and prevention of tumor recurrence occurs because Ivermectin intervenes in those signaling pathways that maintain stem cell characteristics in cancer cells. Ivermectin shows potential use as a complementary drug to combat drug resistance, as it inhibits ABC transporter function in CSCs.

Reversal of multidrug resistance (MDR)

Cancer cells develop multidrug resistance through active transport using efflux transporters, allowing them to effectively pump out drugs, becoming a key barrier to chemotherapy treatment. (64)
Ivermectin effectively stops the function of P-glycoprotein (P-gp), as well as other ATP-binding transporters (ABCs) that lead to MDR in various types of cancer.
Combining Ivermectin treatment with chemotherapeutic drugs leads to better outcomes, as the drug blocks the ejection pumps that normally pump out these drugs. The additive effects of Ivermectin with conventional cancer chemotherapy drugs confirm its potential to become an effective treatment strategy for penetrating MDR.

Ivermectin and the immune system

Synergy with immune therapies

Recent studies show that ivermectin acts as an immune regulator, making it suitable for supporting immunotherapy.
Studies show that ivermectin enhances the effects of immune checkpoint inhibitor drugs, such as anti-PD-1 and anti-CTLA-4, by restoring immunosuppression of the tumor environment.
Activation of cytotoxic T cells increases, while dendritic cells increase antigen presentation, as Ivermectin simultaneously reduces the number of regulatory T cells that suppress immune responses.
Ivermectin modifies immune pathways, allowing it to turn immunologically „cold” tumors into „hot” ones, which enhances their response to immunotherapy.

Effects on tumor-associated macrophages (TAM)

Immune cells known as tumor-associated macrophages (TAMs) have two different functions in cancer cells, as they can either support tumors through the M2 phenotype or help fight tumors through the M1 phenotype.
Ivermectin has shown the ability to convert TAMs with pro-tumor M2 functions into anti-tumor M1 cells, resulting in stronger immune monitoring and tumor destruction.
The macrophage polarization effect generated by ivermectin treatment creates an immunostimulatory context that improves the efficacy of existing immunotherapeutic approaches.

Comparative analysis

Ivermectin vs. other reformulated drugs

A number of drugs from various sources, such as metformin, hydroxychloroquine and fenbendazol, have been evaluated as potential anticancer drugs n.

• Diabetic patients use metformin as their primary drug, but studies show its anti-diabetic properties by inhibiting mTOR signaling while reducing insulin-like growth factor (IGF) activity.
• Metformin acts on the metabolic cascade, but Ivermectin acts through two different mechanisms involving apoptosis induction and immune modulation.
• Hydroxychloroquine has antimalarial capabilities that show potential to stop autophagy in cancer cells to improve the efficacy of chemotherapy.
• The antitumor properties of hydroxychloroquine differ from ivermectin in that it does not show a significant effect on CSCs or reverse MDR.
• Fenbendazol has shown anti-tumor properties due to its dual action of disrupting microtubules combined with inhibiting glucose uptake after being developed as an anti-parasitic drug.
• The main target of fenbendazolem treatment is metabolic processes, and its therapeutic scope seems more limited than that of ivermectin.

Side effects and toxicity profiles

It is well known that ivermectin has a safe profile, but administrators must still consider its potential unknown effects when used in high doses.
Potential toxic effects include:

• Excessive intake of ivermectin may modify GABA-gated chloride channel function, resulting in dizziness along with ataxia and mental confusion.
• Medical evidence suggests that taking ivermectin for an extended period of time may cause a mild increase in liver enzymes.
• The drug Ivermectin can potentially modify drug metabolism by interacting with drugs that are substrates of cytochrome P450.
• Clinical trials on appropriate doses of ivermectin for cancer treatment should continue, as the drug shows a higher level of safety compared to typical chemotherapy drugs.

Clinical research roadblocks and future research challenges

In conducting clinical trials, Ivermectin has faced major obstacles in moving from preclinical data to clinical practice. The lack of large-scale randomized controlled trials (RCTs) prevents regulators from approving the use of the drug.
The generic nature of Ivermectin prevents pharmaceutical companies from finding sufficient financial reasons to initiate clinical trials. The oncology community is showing resistance to accepting Ivermectin as an anti-cancer therapy because of ongoing debates about its COVID-19 treatment applications.

Potential biomarkers of ivermectin sensitivity

Identification of biomarkers capable of predicting response to ivermectin will lead to better patient selection in future studies.

Potential biomarkers include:

• Wnt/β-catenin mutations in ivermectin-sensitive tumors. Measurement of P-glycoprotein expression levels demonstrates ability to reverse MDR. Study of immune patterns to predict compliance with checkpoint blockers.
• Researchers should now direct studies to develop specific strategies that integrate these biomarkers with specific ivermectin-based models of care to ensure optimal outcomes for patients using this therapy.

Preclinical (animal) vs. clinical (human) studies

The potential of ivermectin as an anti-cancer drug needs to be evaluated based on a clear distinction between laboratory animal studies and human clinical trials. The table below identifies the key differences between the two studies.

Combination therapies: Ivermectin with conventional cancer treatments

The use of ivermectin shows the most promising potential as a device that enhances conventional anticancer therapies in combination. Ivermectin targets multiple pathways of cancer progression, thus demonstrating the ability to enhance current anti-cancer therapies while preventing therapeutic resistance.
Some of the different mechanisms of action of ivermectin in combination with standard cancer treatments are listed below:

Increasing the effectiveness of chemotherapy

Studies show that ivermectin treatment increases the sensitivity of cancer cells to standard chemotherapeutic drugs – doxorubicin and paclitaxel along with cisplatin.
Preventing cancer cell survival becomes possible because Ivermectin blocks important pathways such as PI3K/Akt/mTOR signaling while causing oxidative damage to cancer cells.
Chemotherapy treatment in cancer patients leads to increased cell apoptosis, making it possible to lower drug doses and reduce toxicity to healthy tissues.

Improving the results of immunotherapy

The immune system benefits from ivermectin administration because it modifies immune responses, which enhances the effectiveness of PD-1 and CTLA-4 immune checkpoint inhibitors.
The combination of enhancing T-lymphocyte activation and reducing immunosuppression of the tumor microenvironment through ivermectin administration enables better defense of cancer cells in the human body. Studies show that ivermectin helps mature dendritic cells while improving antigen presentation, thereby enhancing anti-tumor defense.

Overcome multidrug resistance

A major obstacle during anti-cancer therapy is the development of cancer cell resistance to various drugs.
Ivermectin has shown efficacy in slowing the activity of the drug efflux pump, including P-glycoprotein along with ABC transporters, which remove chemotherapeutic substances from cancer cells.
The effectiveness of chemotherapeutic drugs against resistant cancers improves with ivermectin treatment, as the drug prevents the elimination of chemotherapeutic agents by cancer cells.

Reduction of tumor stemness

A small subset of cancer stem cells called CSCs enable tumor stemness to persist, contributing to drug resistance, spread and relapse.
Recent findings show that Ivermectin acts as a specific inhibitor of CSC-like properties due to its ability to suppress Wnt/β-catenin and Hedgehog signaling and matrix-associated markers. Destroying CSCs through Ivermectin treatment would enhance conventional therapies, reducing both relapse rates and improving patient survival statistics.
When used in combination, these different treatments offer new opportunities to develop therapies that can improve patient health outcomes in many types of cancer.
Additional studies are needed to confirm these findings along with the development of optimal drug protocols using Ivermectin in medicine.

Clinical trials and future prospects

After promising preliminary laboratory results on ivermectin's anticancer properties, targeted human clinical trials should be conducted to test its safety limits, as well as the most effective dosage and treatment potential in humans.
Researchers are conducting a number of clinical trials and preparing additional research projects to evaluate ivermectin treatment for various types of cancer.

Phase II study in glioblastoma multiforme

Researchers are conducting a Phase II clinical trial of ivermectin for the treatment of glioma patients, evaluating treatment outcomes, including tumor size reduction along with medical survival time. (65)
Studies examining ivermectin as a potential therapy for glioblastoma multiforme must be conducted immediately, as the disease is aggressive and standard drugs do not provide adequate control.

Breast cancer research

Medical researchers are conducting studies combining ivermectin with conventional breast cancer chemotherapy protocols.
The study aims to see how Ivermectin affects tumor growth, as well as chemotherapy response rates and patient survival time. Ivermectin is showing evidence of overcoming some of the resistance factors that some studies say reduce the effectiveness of current treatment options.

 Research on colorectal cancer

Researchers conducted a colorectal cancer study using ivermectin, combining the drug with EGFR and VEGF inhibitors.
Research experts are testing Ivermectin to enhance the potency of basic drugs while evaluating its ability to minimize the spread of cancer cells and increase treatment efficacy. Such successful results would establish Ivermectin as an important therapeutic agent in the treatment of colorectal cancer. (66)

Other potential studies

Additional studies are using ivermectin to determine its effects on pancreatic cancer, lung cancer and various forms of leukemia and lymphoma in early clinical trials. The drug shows unique potential in oncology because it affects several different cancer-causing pathways.
The results of clinical trials will serve as the primary criteria for determining whether Ivermectin can achieve widespread clinical use in cancer treatment. Before ivermectin can become a common option for cancer treatment, medical authorities must grant regulatory approval through safety testing and extensive clinical trials.

Conclusions: The way forward for ivermectin in oncology

Initially considered an anti-parasitic drug, ivermectin has recently gained attention as a potential therapeutic agent for cancer treatment. Scientific evidence shows that ivermectin induces cell death while maintaining the cell cycle and affecting immune responses, which accounts for its potential value in cancer treatment.
Clinical interest in ivermectin as an anti-cancer therapy has grown because it counteracts tumor growth and enhances standard treatment effects while attacking the cancer's underlying immunity and immune evasion mechanisms.
Current laboratory studies show that ivermectin is effective against several types of cancer, including lung cancer, breast cancer, gliomas and leukemias. The medical use of ivermectin in cancer treatment requires extensive clinical trial results to establish safe dosage recommendations along with standard anticancer drug evaluations.
Despite its potential, challenges remain. Finances have not been sufficient motivation for pharmaceutical companies to conduct clinical trials, as Ivermectin falls into the generic category. An in-depth evaluation of the drug's response and side effects, as well as individual patients' responses to treatment, is needed.
Detailed safety assessments and pharmacokinetic testing by pharmaceutical companies will determine the most favorable route for incorporating ivermectin into cancer treatment. Researchers are actively conducting ongoing studies that explore the tumor suppressive potential of Ivermectin and its effects on immune responses, as well as mechanisms for reversing drug resistance.
The therapeutic potency and bioavailability of ivermectin can be improved by developing sophisticated nanoparticle-based dosing methods along with liposomal formulations. Selecting appropriate biomarkers for therapy would increase efficacy rates while reducing treatment risks.
Exploring Ivermectin's applications in cancer treatment is an active area of promising future research. Comprehensive scientific testing would allow Ivermectin to become an important anti-cancer drug that could provide new perspectives for patients struggling with resistant forms of cancer.

Disclaimer

This article was written for educational purposes and is intended to raise awareness of the substance under discussion. It is important to note that the article is about the substance in general - it is not a description of a specific product (chemical reagent). We do not suggest using chemical reagents on humans - this is prohibited by law. For a product to be used for treatment, it must be registered as a drug. The information in the text is based on available scientific research and is not intended to serve as medical advice or promote self-medication. The reader should consult any health and treatment decisions with a qualified health professional.

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