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

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)

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.

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.

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.