Molecular targets of ivermectin as a potential repurposed drug in cancer therapy: A scoping review

Abstract

BACKGROUND

Ivermectin, an antiparasitic drug, has recently gained attention as a potential candidate for repurposing in cancer therapy. However, the clinical safety and implications of its use in this context remain inadequately explored.

AIM

To map existing preclinical evidence on ivermectin’s anticancer mechanisms, evaluate its therapeutic role in cancer treatment, and identify known or potential drug interactions relevant to oncology practice.

METHODS

A systematic search was conducted across PubMed and EMBASE, covering publications from January 2000 up to the present to identify studies eligible for inclusion in accordance with PRISMA extension for Scoping Reviews guidelines.

RESULTS

A total of 43 studies were included in this review. The data extracted from the studies covered ivermectin therapy across breast, colorectal, glioblastoma, and hematologic malignancies. Most studies showed that Ivermectin exerts its anticancer effects by inhibiting P-glycoprotein and tumor proliferation, mitochondrial dysfunction, and modulating various oncogenic molecular pathways.

CONCLUSION

Ivermectin shows potential as a repurposed anticancer agent, particularly as an adjunct to conventional therapies. However, robust clinical trials are needed to validate efficacy, optimize dosing, and ensure safety. This review provides a foundational framework for future translational and clinical research in oncology.

Key Words: Ivermectin; Cancer; Ivermectin-drug interactions; Drug repurposing; Molecular targets

Core Tip: Ivermectin shows promise as a repurposed anticancer agent by targeting multiple molecular pathways, including inhibition of Wnt/β-catenin signaling, modulation of p21-activated kinase 1 activity, and induction of mitochondrial dysfunction. Its ability to induce apoptosis, suppress tumor growth, and overcome drug resistance highlights its therapeutic potential across diverse cancer types. Available clinical evidence is preliminary and requires rigorous clinical validation to establish safety, efficacy, and optimal dosing in oncology. Ivermectin’s multitargeted mechanisms make it a possible candidate for cancer therapy, but translation into clinical practice demands cautious, evidence-based evaluation through well-designed clinical trials.

INTRODUCTION

Cancer remains a leading cause of mortality worldwide, despite the major strides in cancer therapy[1]. One emerging strategy to overcome barriers in cancer treatment is drug repurposing, a novel approach that seeks to identify new uses for existing, clinically approved drugs[2].

Ivermectin, a macrocyclic lactone derived from Streptomyces avermitilis, was initially developed as an antiparasitic agent but has since been recognized for more than just its antiparasitic effect[3]. An increasing number of studies indicate that Ivermectin may have anti-cancer effects in various types of tumors, with some of the proposed mechanisms including the suppression of cell proliferation through reactive oxygen species (ROS)-mediated mitochondrial apoptosis pathway and the induction of S phase arrest in cancer cells[4-6]. Ivermectin can also induce cytostatic autophagy by promoting ubiquitination-mediated degradation of p21-activated kinase 1 (PAK1), which inhibits the protein kinase B-mammalian target of rapamycin (mTOR) signaling pathway[7].

Published studies highlight ivermectin’s ability to directly target multiple oncogenic pathways, underscoring its potential as an anticancer agent[8]. When combined with other cancer drugs, it improves clinical outcomes and reduces recurrence[9].

Ivermectin interacts with other cancer drugs in combination therapies in three ways: Additively, antagonistically, or synergistically[10]. These interactions promote efficacy and selectivity but lower the toxicity and resistance to cancer drugs[11].

It is important to note that despite several successful in vitro studies involving the use of Ivermectin in cancer therapy, there remain challenges in translating these results into clinical practice[12]. Variability in pharmacokinetics among patients makes it difficult to achieve therapeutic concentrations in vivo, and differences between cell lines and human cells pose a challenge in predicting drug responses in humans[13,14].

While recent studies on the use of Ivermectin in cancer therapy show promise, the existing evidence remains fragmented and predominantly preclinical. Current research varies significantly in terms of cancer types, cell line models, and dosing regimens. This scoping review aims to map the available evidence on the use of ivermectin in cancer therapy. Specifically, it seeks to: Classify existing studies by cancer type and study design that explore ivermectin’s anticancer potential; summarize reported mechanisms of action and outcomes of drug-drug interactions; and identify research gaps to guide future preclinical and clinical investigations.

MATERIALS AND METHODS

Registration and search strategy

This scoping review was conducted in accordance with the PRISMA guidelines for scoping review and was registered in the Open Science Framework (https://osf.io/g8vk2). Literature searches were conducted through PubMed and EMBASE to identify eligible studies for this article, covering all publications from January 2000 up to the present. The search strategy focused on five core concepts: Ivermectin, cancer, preclinical evidence, clinical studies, and drug interactions. Key terms included “ivermectin”, “cancer”, “tumor”, “in vitro”, “clinical trial”, and “drug interaction”. Boolean operators (AND/OR) and truncation were used to enhance search sensitivity. Table 1 presents the databases searched and the corresponding Medical Subject Headings terms employed.

Table 1 Databases and search terms used during the study.

Database	Search date	Search terms
PubMed	September 17, 2025	(Ivermectin[MeSH Terms] OR ivermectin OR avermectin) AND (Neoplasms[MeSH Terms] OR cancer OR carcinoma OR tumor OR neoplasm OR malignan OR oncology) AND (therapy OR treatment OR intervention OR effect OR outcome OR response OR inhibition OR cytotoxicity OR anti-cancer OR anticancer OR anti-tumor OR antitumor)
EMBASE	September 17, 2025	Ivermectin/OR ivermectin.mp. OR (ivermect OR stromectol OR mectizan OR sklice).tw,kw. AND exp neoplasm/OR (cancer OR tumor OR tumour OR neoplas OR malignan OR carcinoma OR sarcoma OR lymphoma OR leukemia OR leukaemia OR oncology).tw,kw. AND exp cancer therapy/OR exp antineoplastic therapy/OR (therapOR treat OR adjunct OR adjuvant OR drug reposition OR drug repurpos)

Eligibility criteria

Experimental and clinical studies that examined the anticancer activity of ivermectin were included in this review. This included in vitro and in vivo preclinical studies, clinical observation studies, as well as mechanistically important reviews of ivermectin with other cancer treatment therapies. The results of studies included in the review had to report cell viability, tumor response, mechanistic pathways, or drug interactions. Articles of no relevance to cancer, commentary papers lacking data, duplicates, and articles lacking adequate methodological and outcome description were filtered out to ensure relevance and extraction of the major findings.

Title and abstract screening

Records were uploaded into the Rayyan software for systematic and scoping reviews to collaborate among authors. The Duplicate citations were manually removed before screening started. Two independent reviewers, Roy Olunga and Reinhard Kipkoech, conducted the title and abstract screening, and the disagreements were resolved through a consensus with a third review author, Lydia Mutanu.

Full text screening

After title and abstract screening, full-text records were obtained to assess relevance. Records not published in English or without a full text were excluded at this stage. Efforts were made to secure unavailable records. Two independent reviewers, Lydia Mutanu and Gloria Natalia, conducted the full text review, resolving disagreements with a third author, Roy Olunga. Duplicated data were assessed, prioritizing the original study when multiple sources reported the same findings. Figure 1 demonstrates the entire screening process.

Figure 1 PRISMA-scoping reviews flow diagram.

Data extraction

All the relevant articles that passed the screening and inclusion criteria were considered for analysis. Data extraction was conducted by two independent reviewers (Reinhard Kipkoech and Ruth Jepkorir Tai). From each study, the following information was extracted: The surname of the first author, year of publication, study design, type and stage of cancer, ivermectin dosage, duration of follow-up, proposed mechanism of action, molecular pathway targeted, co-administered drug, and the mechanism of drug-drug interaction. Any variances were resolved by consensus with a third review author, Roy Olunga. The extracted data is available upon reasonable request.

Statistical analysis

Descriptive methods were employed to present the data, with tabular summaries provided where appropriate for clarity. Due to the breadth of the search and the heterogeneity of included records, formal critical appraisal was deemed impractical. This decision was made collaboratively by all authors and aligns with the PRISMA extension for Scoping Reviews guidelines.

RESULTS

Study characteristics

A total of 1427 studies were obtained, from which 43 studies were included in this review. Most of the articles were from China[4,5,8-27], followed by the United States[28-31], Japan[32,33], Thailand[34,35], United Kingdom[36,37] Portugal[38], Mexico[39], Poland[40], Taiwan[6], Italy[41], Switzerland[13], Australia[42], South Korea[43], and Ecuador[44]. The cancer types analyzed in this review were prostate cancer, breast cancer, colorectal cancer, ovarian cancer, bladder cancer, glioma, glioblastoma, multiple myeloma, hepatocellular cancer, pancreatic cancer, and esophageal cancer. The studies included were in vivo and in vitro experimental studies, observational studies, preclinical studies, and case reports. The experimental models included human cell lines and mouse models. Two clinical studies were also included in this review. Out of the 43 studies included in this review, drug combinations were directly reported in 28 studies.

Ivermectin dosage and exposure time

The dosage of ivermectin varied widely in the studies included in this review. The in vitro concentration ranged from 0.01 μM to 100 μM, considering both low-dose mechanistic assays and high-dose cytotoxicity testing, with 4-20 μM being the most common concentration. The most commonly reported doses across apoptosis assays, cell-viability assays, and signaling assays across the studies were 5 μM, 10 μM, 15 μM, and 20 μM[4,12,19,27,45]. Higher ivermectin doses (> 40 μM-100 μM) were used in multidrug-resistance reversal assays[30]. Most preclinical studies administered ivermectin at a dosage of 2.5-10 mg/kg over a period of 2-4 weeks, depending on the cancer type and length of the trial. Human observational studies reported lower ivermectin exposure, with a 12 mg dose being administered orally at varying intervals[32] and 1-5 mL being administered intramuscularly[43].

DISCUSSION

Mechanisms of action of ivermectin

Prostate cancer: Ivermectin shows strong anticancer activity in both hormone-sensitive and castration-resistant prostate cancer models. It works by binding to forkhead box A1 and Ku70/Ku80, which are important regulators of androgen receptor (AR) signaling and DNA repair. This binding reduces chromatin accessibility for AR and E2F transcription factor 1, which suppresses their transcriptional activities. Additionally, it impairs the non-homologous end joining and homologous recombination repair pathways by downregulating breast cancer gene 1 and radiation sensitive 51[17], leading to cell cycle arrest in the G0/G1 phase, causing DNA double-strand breaks, and inducing apoptosis[44]. In vitro studies indicate that ivermectin significantly reduces cell viability and colony formation, especially in AR-positive cell lines. In vivo, it suppresses tumor growth in human prostate carcinoma epithelial cell line (22RV1) xenografts and increases markers of DNA damage, such as phosphorylated histone H2AX. Notably, when combined with enzalutamide, ivermectin enhances its antiproliferative effects, lowers its half maximal inhibitory concentration, and increases apoptosis[17].

Ovarian cancer: In chemo-resistant models of high-grade serous ovarian carcinoma, ivermectin interacts and inhibits P-glycoprotein (P-gp), leading to increased intracellular accumulation of paclitaxel and enhancing its cytotoxic effects. Ivermectin synergizes with pitavastatin, promoting apoptosis through the activation of caspase 3 and caspase 7 and modulation of the mevalonate pathway in ovarian cell lines[43]. Additionally, ivermectin inhibits phosphorylation of serine 338 of the kinase rapidly accelerated fibrosarcoma 1, a major target of PAK1, hence its effectiveness in PAK1-dependent ovarian cancer cells[46,47]. While ivermectin alone shows modest activity (with an half maximal inhibitory concentration around 10-20 μmol/L), it significantly enhances apoptosis and reduces cell viability when used in combination with other agents[43].

Bladder cancer: Ivermectin shows strong antiproliferative and pro-apoptotic effects in both non-muscle invasive and muscle-invasive bladder cancer models. It activates the Ataxia-telangiectasia mutated, checkpoint kinase 2, tumor protein p53, and cyclin-dependent kinase inhibitor 1A (p21) signaling pathways, causing DNA damage, increased ROS production, and mitochondrial dysfunction[16]. These effects result in the upregulation of pro-apoptotic proteins such as Bax, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase (PARP), while simultaneously downregulating the anti-apoptotic protein Bcl-2. Importantly, ivermectin exhibits low toxicity to normal urothelial cells, indicating a favorable therapeutic index. It reduces tumor volume and weight in xenograft models without affecting body weight, further reinforcing its potential as a safe adjuvant therapy[6,15].

Hepatocellular carcinoma: In advanced hepatocellular carcinoma, ivermectin targets several oncogenic pathways, including mTOR, signal transducer and activator of transcription 3 (STAT3), epithelial-mesenchymal transition (EMT), and Nanog, SRY-box transcription factor 2, and octamer-binding transcription factor 4 transcription factors. It inhibits cell proliferation, migration, and the formation of stem-like colonies, while also inducing apoptosis[18]. It also causes EMT suppression by increasing E-cadherin and decreasing the expression of vimentin, snail, and slug transcription factors. When combined with sorafenib, ivermectin produces a synergistic effect on tumor suppression both in vitro and in vivo, without adding toxicity[15].

Colorectal cancer: Ivermectin induces apoptosis in colorectal cancer through ROS-mediated mitochondrial pathways. It increases intracellular ROS levels, upregulates pro-apoptotic proteins such as Bax and cleaved PARP, downregulates Bcl-2, and activates caspase-3 and caspase-7. Additionally, it causes S-phase cell cycle arrest[4]. In vincristine-resistant colorectal cancer models, ivermectin inhibits migration and metastasis by suppressing the Wnt, β-catenin, integrin β1, and focal adhesion kinase signaling pathways[40]. These effects are consistent even in models where the epidermal growth factor receptor (EGFR) is knocked out, indicating that the activity of ivermectin is independent of EGFR. Furthermore, combining ivermectin with adriamycin or vincristine enhances these effects, demonstrating a synergistic potential in overcoming drug resistance and inhibiting tumor progression[40].

Cholangiocarcinoma: Ivermectin induces apoptosis, autophagy, and pyroptosis and inhibits proliferation, angiogenesis, and metastasis in cholangiocarcinoma cell lines. It also modulates the tumor microenvironment and cancer stem cells[45]. The molecular pathways targeted in cholangiocarcinoma include PAK1, mTOR, Wnt, β-catenin, EGFR, and STAT3. Ivermectin demonstrates synergistic effects when combined with agents like cisplatin, paclitaxel, and erlotinib, enhancing apoptosis and reversing drug resistance. These interactions are mediated through inhibition of multidrug resistance (MDR) proteins such as P-gp and modulation of EGFR and HER2 signaling[15].

Gastric cancer: Ivermectin induces apoptosis and autophagy, inhibits cell proliferation and angiogenesis, and modulates the expression of cancer stem cell markers in gastric cancer cell lines. Mechanistically, ivermectin directly targets important pathways, including PAK1, mTOR, Wnt, β-catenin, and Yes-associated protein 1[30]. Although specific drug combinations have not been tested in gastric cancer models, ivermectin’s known synergy with drugs like paclitaxel and cisplatin in other cancers suggests there may be potential benefits in combinatorial treatments in gastric cancer[15].

Lung cancer: In lung cancer models, ivermectin induces apoptosis and inhibits proliferation and metastasis. It modulates EGFR and STAT3 signaling, while also enhancing ROS production and mitochondrial dysfunction. While direct drug-drug interaction studies in lung cancer are limited, ivermectin has shown synergy with EGFR inhibitors, such as erlotinib and cetuximab, in other models, suggesting a potential for combination therapy in EGFR-driven lung cancers[15,38]. In non-small cell lung carcinoma, ivermectin interacts with Tel2 C-terminal domain to inhibit Tel2-Tti1-Tti2 complex functions, destabilizes phosphoinositide 3-kinase-related kinases, hence suppressing their signaling activity and inhibiting the growth of cancer cells[34].

Breast cancer: Ivermectin demonstrates a myriad of anticancer effects in both triple-negative and estrogen receptor-positive breast cancer models. It induces G0/G1 cell cycle arrest by downregulating cyclins D and E, and proliferating cell nuclear antigen, and upregulating p21. This process inhibits cell proliferation and reduces clonogenic capacity[44]. Furthermore, ivermectin targets cancer stem-like cells by decreasing aldehyde dehydrogenase expression and promoting apoptosis through mitochondrial dysfunction and the generation of ROS[15,31,37]. It also triggers apoptosis and necrosis through the activation of caspase 1 and caspase 3, PARP activation, and ion flux and pore formation[37]. Additionally, synergistic interactions have been observed with tamoxifen, docetaxel, and cyclophosphamide. These interactions are attributed to the reversal of MDR and complementary antiproliferative effects. Both in vitro and in vivo studies show significant reductions in tumor size and weight, with no noted toxicity. Ivermectin also reduces cancer metastasis by suppressing the EMT pathway in a concentration-dependent manner[40].

Ivermectin inhibits the PAK1/STAT3 pathway to suppress IL-6 gene expression, preventing breast cancer stem cell formation, growth, migration, colony, and mammosphere growth and inducing apoptosis by activation of caspase 3 and caspase 7, and reduction of CD44+/CD24 and aldehyde dehydrogenase-expressing cancer stem cells[48].

Pancreatic cancer: Ivermectin interferes with metabolic and mitochondrial activity in cell models of pancreatic cancer, through significant viability loss of Michigan adenocarcinoma of the pancreas 2 cells[36]. Ivermectin elevates cytosolic Ca²⁺ through purinergic/P2X-pannexin axis stimulation and induction of mitochondrial injury and caspase-dependent apoptosis[38]. Ivermectin also inhibits micropinocytosis, which prevents nutrient scavenging and albumin-dependent growth in nutrient-poor tumors. While it does not suppress the phosphatidylinositol-dependent growth of 3D nutrient-deprived cultures, it does selectively inhibit the growth of the epithelial cancerous component within spheroids[45].

Esophageal cancer: A single treatment with ivermectin induces mitochondrial dysfunction, ROS accumulation, and apoptosis in esophageal squamous cell carcinoma models. It affects stress signaling and promotes the proteasomal degradation of oncogenic kinases, particularly leading to the degradation of PAK1. This process triggers apoptotic events, including the release of apoptosis-inducing factor and cytochrome c, suggesting that ivermectin destabilizes pro-survival kinases through proteasome activity[23]. Furthermore, ivermectin inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, suppressing the transcription of survival and inflammatory genes[5].

Chronic myeloid leukemia: In breakpoint cluster region and abelson murine leukemia viral oncogene homolog 1-driven and tyrosine kinase inhibitor-resistant chronic myeloid leukemia models, ivermectin impairs mitochondrial oxidative phosphorylation, reduces ATP production, and triggers caspase-dependent apoptosis while additionally suppressing pro-survival signaling and reversing drug resistance[24]. Additionally, ivermectin reduces phosphorylation of EGFR family members and downstream effectors, producing G2/M arrest and apoptosis preferentially in flumatinib-resistant cells, suggesting both direct mitochondrial toxicity and suppression of signaling that sustains tyrosine kinase inhibitor resistance[28].

Brain tumors: The literature on glioma indicates that mitochondrial dysfunction, ROS-damage, suppression of mTOR and other survival cascades, cell-cycle arrest, and regulation of cancer-stem-cell programs are central to reducing tumor growth. Ivermectin causes apoptosis and autophagy, ATP and complex-I activity reduction, and modifies multiple signaling nodes such as EGFR/STAT3/PAK1 and ATP-binding cassette (ABC) transporter activity, downstream to caspases and cell-cycle control[15,30,49]. Inhibition of the mTOR pathway and elevated ROS jointly contribute to fatal energetic stress in glioma cells[22]. Additionally, ivermectin’s ability to suppress P-gp activity can be utilized to overcome chemoresistance[12,27]. Table 2 summarizes the mechanism of action of ivermectin in different cancer types.

Table 2 Mechanisms, molecular targets, and drug-drug interactions of ivermectin across different cancer types.

Cancer type	Mechanism of action	Molecular targets	Co-administered drugs	DDI mechanism	Efficacy of combination therapy
Breast cancer	G0/G1 arrest; apoptosis; stem cell inhibition; MDR reversal	Cyclin D/E, PCNA, p21, PAK1/Akt/mTOR, ALDH, ROS	Tamoxifen, docetaxel, cyclophosphamide	MDR inhibition; complementary antiproliferative synergy	Reduced tumor size and weight; enhanced apoptosis; no toxicity
Prostate cancer	Synthetic lethality via FOXA1/Ku70/Ku80; AR/E2F1 suppression; DNA damage	FOXA1, Ku70/Ku80, AR, BRCA1, Rad51	Enzalutamide	Enhanced apoptosis; reduced IC50 of ivermectin	Tumor suppression in vitro and in vivo; increased
Ovarian cancer	Chemoresistance reversal via P-gp inhibition; apoptosis enhancement	P-gp, HMGCR, mutant p53, PAK1/Akt/mTOR, YAP1	Paclitaxel, pitavastatin	Increased intracellular drug retention; synergistic apoptosis	Synergy in resistant lines: Reduced viability, increased caspase activity
Bladder cancer	ATM/p53-mediated apoptosis; ROS generation; mitochondrial dysfunction	ATM/CHK2/p53/p21, Bax/Bcl-2, caspase-3, PARP	None reported	Not applicable	Reduced tumor volume; low toxicity; increased apoptosis markers
HCC	Stemness suppression; EMT inhibition; apoptosis induction	mTOR/STAT3, EMT, Nanog, Sox2, Oct4	Sorafenib	Suppression of mTOR/STAT3 and EMT pathways	Synergistic tumor suppression; reduced migration and stemness markers
Colorectal cancer	ROS-mediated mitochondrial apoptosis; S-phase arrest; migration inhibition	Wnt/β-catenin, Bax/Bcl-2, PARP, caspase-3/7, integrin β1/FAK	Adriamycin, vincristine	EGFR-independent inhibition of metastasis	Synergy in drug-resistant models; reduced viability and migration
Cholangiocarcinoma	Apoptosis, autophagy, pyroptosis; MDR reversal; stem cell modulation	PAK1, Akt/mTOR, EGFR, STAT3, YAP1, Wnt/β-catenin, P2X4/P2X7/NLRP3	Cisplatin, paclitaxel, erlotinib	MDR inhibition; EGFR/HER2 modulation	Enhanced tumor cell death; restored drug sensitivity
Gastric cancer	Apoptosis and autophagy; stem cell suppression; proliferation inhibition	PAK1, Akt/mTOR, Wnt/β-catenin, YAP1	Not reported	Not specified	Inhibition of proliferation and angiogenesis; stem cell suppression
Lung cancer	Apoptosis via ROS and mitochondrial dysfunction; EGFR modulation	EGFR, STAT3, YAP1, ROS pathways	Erlotinib, cetuximab	EGFR/HER2 modulation; MDR reversal	Enhanced apoptosis and drug sensitivity

DDI: Drug-drug interaction; MDR: Multidrug resistance; PCNA: Proliferating cell nuclear antigen; PAK1: P21-activated kinase 1; FAK: Focal adhesion kinase; ATM: Ataxia telangiectasia mutated; FOXA1: Forkhead box A1; YAP1: Yes associated protein 1; HCC: Hepatocellular carcinoma; IC₅₀: Half maximal inhibitory concentration; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin; ALDH: Aldehyde dehydrogenase; ROS: Reactive oxygen species; Ku70: Lupus Ku autoantigen protein p70; Ku80: Lupus Ku autoantigen protein p80; AR: Androgen receptor; BRCA1: Breast cancer gene 1; Rad51: RAD51 recombinase; P-gp: P-glycoprotein; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; CHK2: Checkpoint kinase 2; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; PARP: Poly (ADP-ribose) polymerase; STAT3: Signal transducer and activator of transcription 3; EMT: Epithelial-mesenchymal transition; Nanog: Nanog homeobox; Sox2: SRY-box transcription factor 2; Oct4: Octamer-binding transcription factor 4; EGFR: Epidermal growth factor receptor; P2X4: P2X purinoceptor 4; P2X7: P2X purinoceptor 7; NLRP3: NLR family pyrin domain containing 3; HER2: Human epidermal growth factor receptor 2.

Mechanisms of ivermectin-drug interactions

Synergistic apoptosis induction occurs when ivermectin is co-administered with tamoxifen, paclitaxel, cisplatin, erlotinib, cetuximab, dasatinib, daunorubicin, cytarabine, and docetaxel. The drug combinations enhance tumor cell death, reverse drug resistance, and inhibit MDR proteins such as P-gp and modulate EGFR/HER2 signaling pathways[15].

Ivermectin augments paclitaxel’s cytotoxicity in a dose-dependent manner by inhibiting the activation of NF-κB, a regulator of ABC subfamily B member 1, which codes for the regulator protein P-gp. This leads to increased concentration of paclitaxel in lung adenocarcinoma cells, increasing the cells’ sensitivity to paclitaxel[39]. The combination therapy has a combination index of < 1, supporting ivermectin as a potential chemosensitizer in resistant ovarian cancer therapy[44].

In vitro studies

Pitavastatin and ivermectin demonstrate a synergistic effect in ovarian cancer cell lines through their overlapping effects on apoptotic and autophagic regulation through activation of caspase 3 and caspase 7 activity and annexin V labelling of cancer cells, suppression of the mevalonate pathway that is potentially modulated by mutant p53, and efflux inhibition of the drug through the P-gp pathway[43]. Ivermectin also potentiates bortezomib’s anticancer effects in multiple myeloma models by amplifying ER stress and apoptotic signaling, producing synergistic cytotoxicity that improves tumor suppression in mice, supporting ivermectin as a promising adjuvant to protease inhibitors in multiple myeloma management[21]. With tyrosine kinase inhibitors such as dasatinib and nilotinib, ivermectin breaches the mitochondrial integrity, leading to increased oxidative stress in leukemia cells, making them more susceptible to tyrosine kinase inhibitors[24].

Ivermectin, in combination with docetaxel and cyclophosphamide in estrogen receptor-negative breast cancer cells and tamoxifen in Michigan cancer foundation-7 cells, reduces tumor growth and stem cell markers in vivo[48]. Inhibition of MDR proteins such as P-gp and modulation of EGFR/HER2 signaling when it is co-administered with paclitaxel, cisplatin, erlotinib, cetuximab, dasatinib, daunorubicin, and cytarabine reduces tumor growth and increases sensitivity of tumor cells to chemotherapy[15]. Co-administration of ivermectin with adriamycin or vincristine significantly reverses MDR in multiple cancer types by blocking EGFR/extracellular signal-regulated kinase/protein kinase B/NF-κB signaling and inhibiting MDR1 and P-gp expression both in vitro and in vivo. This combination also inhibits cell migration, leading to tumor regression[40]. When combined with gemcitabine, ivermectin significantly inhibits the growth and colony formation of both gemcitabine-sensitive and resistant cholangiocarcinoma cells, making it a potential alternative for combination therapy with gemcitabine in cholangiocarcinoma[41].

Ivermectin co-administration with dichloroacetate, omeprazole, or tamoxifen enhances mitochondrial dysfunction and ROS generation, which amplifies apoptosis and reduces tumor progression in patients with advanced chemo-resistant malignancies[38]. With paclitaxel co-administration, ivermectin increases the sensitivity of paclitaxel-resistant cancer cells by inhibiting the activation of NF-κB that regulates ABC subfamily B member 1, which is responsible for P-gp regulation[39]. Ivermectin potentiates recombinant methioninase’s cytotoxicity by depriving cells of methionine, leading to oxidative stress that effectively kills Michigan adenocarcinoma of the pancreas 2 pancreatic cancer cells in vitro[35].

Ivermectin enhances the sensitivity of ovarian cancer cells to tamoxifen and fulvestrant by blocking HE4 nuclear import, making it an adjunct to hormonal therapy in HE4-driven antiestrogen-resistant ovarian cancer[36]. When used together with sorafenib in hepatocellular carcinoma stem cells, ivermectin suppresses the mTOR/STAT3 and EMT pathways, inhibiting tumor growth and reducing tumor metastatic potential[50]. Ivermectin also enhances cisplatin efficacy in chemo-resistant ovarian cancer and esophageal squamous cell carcinoma by inducing apoptosis through caspase 3 and PARP activation[23,25].

The synergistic effects of ivermectin and recombinant methioninase are cytotoxic to human pancreatic cancer cells. Rujimongkon et al[41] reported an 80% reduction in the clonality of cancer cells with the combination therapy of ivermectin and recombinant methioninase as compared to the single treatment of either ivermectin (45%) or recombinant methioninase (37%). Ivermectin inhibits vimentin and Snail protein, as well as cellular mobility by over 50% in 24 hours, suggesting an anti-migratory and anti-invasive property of this drug in endocrine-resistant cancer models.

Doxorubicin and ivermectin combination therapy rapidly kills cancer cells due to increased ROS production that is mediated by mitochondrial depolarization[29]. Table 3 summarizes the in vitro efficacy outcomes of ivermectin-drug interaction.

Table 3 Summary of in vitro efficacy outcomes of ivermectin-drug interaction.

In-vitro cell lines in study	Drug(s) co-administered with ivermectin	Primary outcomes
Ovarian cancer	Pitavastatin	Synergy: Potentiating pitavastatin’s apoptotic effects and reduced cell viability
Urothelial carcinoma	Z-VAD-FMK (pan-caspase inhibitor)	Inhibited ivermectin-induced apoptosis, confirming Ivermectin’s caspase dependence
		Enhanced ivermectin’s apoptotic effect
	SP600125 (JNK inhibitor)	Reduced cell viability
	PD98059 (ERK inhibitor)	No synergistic effect
High-grade serous carcinoma	Paclitaxel	Synergy: Augmenting paclitaxel-induced cytotoxicity and apoptosis, with decreased cell viability
Human cholangiocarcinoma	Gemcitabine	Apoptosis induction in gemcitabine-resistant cells through S-phase arrest and inhibition of proliferation
		Suppression of colony formation
Human pancreatic cancer	rMETase	Synergistic: Reduced cell viability by about 80% compared to about 45% using ivermectin alone and about 37% using rMETase alone
Human breast cancer	Tamoxifen	Pharmacodynamic synergy: Lower doses of tamoxifen were required to inhibit proliferation in resistant cell lines through reduced expression of snail, vimentin, LRP6, and Wnt5a/b on western blot assay
Human CML	Flumatinib	Increased apoptosis
		Increased autophagic flux in flumatinib-resistant CML
Melanoma	Bafilomycin A1, acetyl cysteine (autophagy inhibitors)	Enhanced ivermectin-induced autophagy
Breast cancer(majorly), but also melanoma, colon adenocarcinoma, pancreatic cancer, head and neck cancer, leukemia, and prostate cancer	Doxorubicin, paclitaxel	Rapid synergistic toxicity to cancer cells
Human neuroblastoma	Cyclosporin A (MDR1 inhibitor), MK571 (MRP inhibitor), Ko143 (BCRP inhibitor, negative control)	High-affinity inhibition of MDR1
		Moderate inhibition of MRP
Human cancer cell lines	Tamoxifen, paclitaxel, cisplatin, erlotinib, cetuximab, dasatinib, daunorubicin, cytarabine, docetaxel	Synergistic effects via enhanced apoptosis, reversal of drug resistance, and inhibition of multi-drug resistance proteins

BCRP: Breast cancer resistance protein; CML: Chronic myeloid leukemia; ERK: Extracellular signal-regulated kinase; JNK: C-Jun N-terminal kinase; Ko143: CAS 461054-93-3; LRP6: Low-density lipoprotein receptor-related protein 6; MDR1: P-glycoprotein inhibitors MK-571 (L-660711); MRP: Multidrug resistance-associated protein; rMETase: Recombinant methioninase; Z-VAD-FMK: Carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone.

In vivo studies

Ivermectin in combination with several chemotherapeutic agents, such as tamoxifen, paclitaxel, cisplatin, erlotinib, cetuximab, dasatinib, daunorubicin, cytarabine, and docetaxel, shows strong anticancer efficacy in different in vivo models. Ivermectin, in combination with the aforementioned drugs, inhibits tumor growth, metastasis, and angiogenesis significantly in nude mice models as well as Mob1b+/- mice bearing liver cancer[15]. Ivermectin in combination with docetaxel, cyclophosphamide, and tamoxifen significantly decreases tumor growth by 63% and tumor weight by 56% in a murine JC breast cancer model of Balb/c mice[45]. These suggest that ivermectin enhances the cytotoxic action of multiple chemotherapeutic agents by targeting complementary signaling pathways involved in tumor proliferation and angiogenesis.

The combination of ivermectin and enzalutamide shows increased antiproliferative effects mediated by modulations of AR signaling[17]. Ivermectin significantly suppresses and reversibly inhibits tumor growth in vivo without causing systemic toxicity when combined with sorafenib[18]. Co-administration of adriamycin and vincristine with ivermectin inhibits tumor-cell migration and induces significant tumor regression with no observable toxicity[40]. Table 4 summarizes the in vivo efficacy outcomes of ivermectin-drug interaction.

Table 4 Summary of in vivo efficacy outcomes of ivermectin-drug interaction.

Animal model	Tumor type	Drug(s) co-administered with ivermectin	Primary outcomes
Nude mice, Mob1b+/- mice	Liver cancer	Tamoxifen, paclitaxel, cisplatin, erlotinib, cetuximab, dasatinib, daunorubicin, cytarabine, docetaxel	Improved tumor suppression
Balb/c mice (murine JC breast cancer model)	Breast cancer (triple negative, and ER positive), ovarian cancer, prostate cancer	Docetaxel, cyclophosphamide, tamoxifen	Synergy with all 3 drugs with decreased tumor size
Xenograft mouse model (BALB/c-nude mice) using 22RV1 cells in castrated mice	Prostate cancer: Models used include hormonesensitive (LNCaP), castrationresistant prostate cancer (C42), and ARvariant positive CRPC (22RV1)	Enzalutamide	Enhanced antiproliferative effect
			Decreased Ki67 and PSA staining
			Increased γH2A.X in tumor tissue
3D cell culture model	High-grade serous carcinoma (ovarian cancer; chemoresistant)	Paclitaxel	No in vivo survival or tumor data
SNU-182 xenograft in SCID mice	Advanced hepatocellular carcinoma	Sorafenib	Suppressed and reversed tumor growth without toxicity compared to monotherapy
Xenograft models in BALB/c nude mice	Multiple cancers, mainly focusing on multidrug-resistant colorectal cancer (HCT8/VCR)	Adriamycin, vincristine	Inhibited cell migration
6-week-old male BALB/c nude mice xenografts (KYSE30 cells)	Esophageal squamous cell carcinoma	Chloroquine, tocopherol	Chloroquine reduced ivermectin cytotoxicity
			Tocopherol restored cell viability, reducing ivermectin efficacy
Mouse xenograft models of human MM cell line ARD (female 7-week-old severe immunodeficient NOD-Prkdcscid IL2rgtm1/Bcgen mice); toxicity: Balb/c mice	Multiple myeloma	Bortezomib (proteasome inhibitor)	Synergistic cytotoxicity with enhanced tumor growth inhibition
Xenografts in nude mice using KYSE150 cells	ESCC, including models of metastasis (lung metastasis)	Cisplatin and 5-fluorouracil	Increased sensitivity of cancer cells to cisplatin and 5-fluorouracil
			Decreased Ki67 staining in tumor tissue
In vivo xenograft leukemia (K562) model	CML (BCR-ABL positive)	Dasatinib, nilotinib	Improved tumor inhibition with drug combination

CRPC: Castration-resistant prostate cancer; ER: Estrogen receptor; ESCC: Esophageal squamous cell carcinoma; Ki-67: Antigen Kiel 67; MOB1B: MOB kinase activator 1B; MM: Multiple myeloma; LNCaP: Lymph node carcinoma of the prostate; PSA: Prostate-specific antigen; SCID: Severe combined immunodeficiency; CML: Chronic myeloid leukemia; JC: Junctional complex; AR: Androgen receptor; HCT8: Ileocecal adenocarcinoma cell line; VCR: Vincristine; ARD: Acid-related disorders; NOD: Non-obese diabetic; BCR: Breakpoint cluster region; ABL: Abelson murine leukemia viral oncogene homolog.

Clinical evidence of ivermectin’s anticancer effects

A published case series evaluated a combination regimen of dichloroacetate, omeprazole, tamoxifen, and ivermectin in three patients with advanced metastatic breast cancer, osteosarcoma, and lung adenocarcinoma, highlighting its potential therapeutic impact across diverse malignancies with pleural, pulmonary, lymphatic, bone, and brain involvement[39].

The combination drug regimen promoted tumor cell apoptosis and inhibited tumor growth. Tumor markers showed improvement, as carcinoembryonic antigen levels reduced from 12.9 to 7.3, and cancer antigen 15-3 from 302.3 to 229.4 within three months. The patient’s functional capacity, pleural effusions, and symptoms also showed improvement, although imaging studies did not demonstrate a significant decrease in tumor size and mass[39].

A descriptive study in Ecuador revealed that within three months of chemotherapy, cancer patients between 18 years old and 94 years old (n = 48) using veterinary ivermectin (1-5 mL intramuscularly) had subjective responses of general wellness, vigor, and symptomatic relief in > 81.25% of the study participants[51]. Mild Side effects of patient wellness, such as fatigue, malaise, nausea, dizziness, nervousness, lightheartedness, and apprehensiveness, were noted in approximately 8.3% of the study population. Importantly, no severe adverse events were documented, suggesting that ivermectin was well tolerated in this context[51]. However, we note that the findings from this study need to be validated, given its assessment of veterinary and not human formulations and the absence of clear oncologic outcomes and endpoints.

Gaps and limitations

The existing evidence base of ivermectin use in cancer treatment suggests critical weaknesses and limitations that, taken together, make it difficult to draw solid conclusions regarding its clinical therapeutic potential. Most importantly, preclinical research is prevailing in the literature, with very limited clinical research and no properly designed phase I or II trial to determine safety, dosing, or pharmacokinetic behavior in cancer patients. Available clinical research is insignificant and mostly anecdotal. Some of the preclinical studies included in this article do not provide information regarding dosing rationale, duration of treatment, and randomization and blinding. Mechanistic results in this review, though encouraging, are in general founded on single-model experiments and have not been well confirmed by gene editing or replication in a variety of different types of cancer. Also, numerous in vitro experiments utilize drug concentrations that are much higher than concentrations that are safely attainable in humans, which restricts translational applicability. Variability in outcome measures-cell viability, apoptosis, colony formation, or tumor volume-additionally hinders cross-study comparison and synthesis.

Oncology-specific toxicity and safety studies are also scarce. Very few studies investigate organ-level toxicity, therapeutic index, or long-term toxicity in tumor-bearing models. Publication bias and insufficient diversity of experiment sites and tumor biology are a concern because most of the studies are based on a small number of geographic locations, especially in China.

Recommendations

Clinical trials involving ivermectin as an anticancer agent in the early phase are urgently required to assess the feasibility of the anticancer agent and profile its safety in cancer. The use of more clinically relevant models, which include patient-derived xenografts and organoids, would enhance translational validity. Lastly, in-depth toxicity investigations and the ongoing investigation into novel formulations that have the potential of reaching effective drug concentrations in the body can assist in closing the gap between promising preclinical studies and practical clinical use.

CONCLUSION

Ivermectin shows promising anticancer effects across diverse preclinical models, but meaningful clinical translation remains unproven. Significant evidence gaps, inconsistent methodologies, and limited safety data highlight the need for rigorous trials and standardized research. Well-designed clinical, mechanistic, and combination studies are essential to determine ivermectin’s true therapeutic potential in oncology.