Pyrvinium Pamoate: An Anti Worm Drug with Important Anti Cancer Potential


Pyrvinium Pamoate (PP) (a quinoline-derived cyanine dye) is an relatively non toxic anthelmintic drug, FDA-approved, sold over the counter in countries like Sweden, Norway, Denmark used to treat pinworms in humans and animals.

pyrviniumDuring the recent years this compound has been shown to effectively inhibit various cancer cells types such as brain, colon/colorectal, breast, prostate, etc. and patented as a treatment of cancers such as adrenocortical, hepatocellular, hepatoblastoma, malignant melanoma, ovarian, Wilm’s tumor, Barrett’s esophageal, glioma, bladder, breast, gastric, head & neck, lung cell, mesothelioma, and cervical cancers due to its potential to inhibit Wnt activity in the cells of cancers (Wnt pathway is an important signaling pathway specifically relevant when targeting cancer stem cells) (Ref.).

My specific interest in  Pyrvinium was triggered by a very recent (2015) article published in the well known journal Nature. This article presents research performed by scientists in Japan who developed a novel high throughput drug screening system to identify compounds with strong anti-tumor effect, in this case focused on lymphoma. Following the screening of 2613 known pharmacologically active substance and off-patent drugs, including most of well know chemotheraphies, tehy found out one element that was standing out in terms of anti cancer effectiveness. That was Pyrvinium Pamoate. (Ref.)
In the Supplemental Table 3 of this article you will find a list with the top drugs identified. Following this finding, the researchers have also tested the effect of Pyrvinium on the DLB1 xenograft and they concluded the following: “A single administration was enough for tumor disappearance (Fig. 3D), demonstrating the high anti-tumor activity of PP”

PP is an effective element against cancer stem cells (CSC) due to reason explain below, in the Mechanisms section.

PP was shown and patented as an agent to promote wound healing and repair (Ref.)


  • inhibited glutathione supply from stromal cells to lymphoma cells (Ref.)
  • inhibits WNT signaling via activation of casein kinase 1α (CK-1α – a key kinase that phosphorylates β-catenin for degradation) (Ref.)
  • inhibition of cancer stem cells (via the down-regulation of EMT) due to inhibition of WNT signaling (EMT has been shown to be a downstream target of WNT) (Ref.)
  • non-competitive androgen receptor inhibitor (Ref.)
  • inhibitor of NADH-fumarate reductase system, a metabolic system in mitochondria (Ref.) Indeed data suggest that, contrary to the classical Warburg view,tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an “Achilles heel” for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations. (Ref.)
    • anti-cancer drug targeting mitochondrial respiration (Ref.)
  • can sensitize tumor cells to radiation therapy (Ref.)
  • Pyrvinium targets autophagy addiction to promote cancer cell death (Ref.)


As capsule, commercially available as antiworm over the counter medicine in Sweeden, Norway, Danemark under the name Vanquin, for example:

In Germany under brand name MOLEVAC:

As solution, Pyrcon brand in Germany, over the counter (maybe this one can be nebulized? – I have to check the content):

As it can be seen, it is a very low cost drug. It may be found in other countries as well.

In powder form, it is available at western chemical suppliers but expensive®ion=NL&focus=product Alternatively, it is available at Chinese suppliers at a cost of about 3o0USD for 10g of substance which should be enough for applications other than oral administrations.
When ordering from chemical suppliers we need to ask for the following CAS number 3546-41-6.

Safety and Warnings:

Tablets should be swallowed whole to avoid staining of teeth. This drug will color the stool a bright red which is not harmful to the patient. The compound is a strong red dye so it will color anything – so be aware of that but not afraid since is not harmful (Ref.).

Dose & Application:

Oral administration:

Typically, this drug is administrated orally. However, its bio-availability seems to be very low (Ref.). This to me means that even if it is able to kill most of the cancers, it may also not reach most of them at high enough dose!?

Yet, taken orally maybe very relevant to all forms of cancers that can easily be reached in that way, i.e. gastric, colon, colorectal, blader and possibly hepatocellular.

The typical dose suggested for human usage is 5mg/kg/day (which results in an intestinal drug concentration of ~100μM (Ref.) while 1 μM has been shown to induced strong cell death in lymphoma (Ref.)). That means 250mg/day for a 50kg person. The maximum dose suggested for daily administration is 350mg/day regardless of the weight. I have to further investigate how much we can go beyond this dose and still be safe (remember that for e.g. Mebendazole the daily suggested dose is 200mg but clinics administrated to humans >1000mg/day and found that to be safe – In addition I do not see why there would be a safety issue at higher doses since it is anyway not well absorbed).

The capsules are usually of 50mg and the 5mg/kg/day (i.e. 5 capsules for a 50kg person) is administrated all at once, one time only. As an anti worm medicine this may be repeated after 2 to 4 weeks (Ref.). As an anti cancer treatment however, I expect this would need to be administrated more often. I have no reference here and my guess is that we may need to take it every day during a week or every other day during two weeks and repeat after e.g. two weeks.

Other ways to administrate:

Topically: For those cancers accessible via topical application we may mix Pyrvinuim powder (crushed capsule? or bought as a powder) with DMSO since it seems to be soluble in DMSO (solubility is >10mg/ml – Ref). Topical administration may even deliver Pyrvinium in to the blood and as a result access other loccations.

IV or Injection: Ultimately, I should also be able to prepare it in an IV form given that it is soluble in DMSO and Ethanol. With that any location can be reached. However, in this case I would still need to clarify what are the safe blood concentration.


There are several publications indicating that the best anti cancer effect of Pyrvinium seems to take place during glucose starvation. (Ref1, Ref2).

Indeed, here is another study stating the same in a different way:”VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose) … the possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion” (Ref.)

2-DG: “in vivo studies show that the combination therapy of pyrvinium with the anticancer and autophagy stimulus agent, 2-deoxy-D-glucose (2-DG), is significantly more effective in inhibiting tumor growth than pyrvinium or 2-DG alone.”

Chemotherapy: “However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR.”

Other References:

Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells.

Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from oxidative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development.

The structure of PP is shown in Fig. 3A. PP was originally approved as an anthelminthic. Recently, it attracted particular attention as an anti-tumor drug since it was revealed to have cytotoxicity against various cancer cell lines. We first confirmed the lymphoma cell-specific cytotoxicity of PP. In the co-culture of DLB1 cells with BLS4, 1 μM PP induced strong cell death, specifically of lymphoma cells (Fig. 3B). GI50 at 48 h of PP for DLB1 cells co-cultured with BLS4 was 0.137 μM, while even 1 μM PP did not significantly affect the viability of BLS4 and GI50 was not determined (Fig. 3C). Next, we examined the effect of PP on the DLB1 xenograft. PP is an anthelminthic for intestinal parasites and administered orally in humans. But its bioavailability is very poor and its systemic absorption hardly occurs in human15. In addition, after the intraperitoneal administration of PP at the maximum tolerated dose (5 mg/kg), the maximum serum level of PP was 99.3 nM at 15 minutes after the injection16, indicating that the blood concentration of PP could not reach to the level expected to be effective for lymphoma by intraperitoneal administration; therefore, we administered PP locally. PP 20 mg/kg was administered directly to the subcutaneous tumors of DLB1 cells and BLS4. A single administration was enough for tumor disappearance (Fig. 3D), demonstrating the high anti-tumor activity of PP in vivo. Furthermore, PP also induced strong growth suppression of the subcutaneous tumor of DLB2 cells, another lymphoma PDX cells, indicating the possible wide range effectiveness of PP for lymphoma cells

Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy

We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (∼10 fold). It was also reported by others to have anti-tumor activity in vivo and selective toxicity against cancer cells under glucose starvation in vitro, but with unknown mechanism. Here, we provide evidence that pyrvinium suppresses the transcriptional activation of GRP78 and GRP94 induced by glucose deprivation or 2-deoxyglucose (2DG, a glycolysis inhibitor), but not by tunicamycin or A23187. Other UPR pathways induced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgene partially protected cells from pyrvinium induced cell death under glucose starvation, suggesting that suppression of the UPR is involved in pyrvinium mediated cytotoxicity under glucose starvation. Xenograft experiments showed rather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR.

Pyrvinium Wound Treatment Methods and Devices

Pyrvinium targets autophagy addiction to promote cancer cell death

Autophagy is a cellular catabolic process by which long-lived proteins and damaged organelles are degradated by lysosomes. Activation of autophagy is an important survival mechanism that protects cancer cells from various stresses, including anticancer agents. Recent studies indicate that pyrvinium pamoate, an FDA-approved antihelminthic drug, exhibits wide-ranging anticancer activity. Here we demonstrate that pyrvinium inhibits autophagy both in vitro and in vivo. We further demonstrate that the inhibition of autophagy is mammalian target of rapamycin independent but depends on the transcriptional inhibition of autophagy genes. Moreover, the combination of pyrvinium with autophagy stimuli improves its toxicity against cancer cells, and pretreatment of cells with 3-MA or siBeclin1 partially protects cells from pyrvinium-induced cell death under glucose starvation, suggesting that targeted autophagy addiction is involved in pyrvinium-mediated cytotoxicity. Finally, in vivo studies show that the combination therapy of pyrvinium with the anticancer and autophagy stimulus agent, 2-deoxy-D-glucose (2-DG), is significantly more effective in inhibiting tumor growth than pyrvinium or 2-DG alone. This study supports a novel cancer therapeutic strategy based on targeting autophagy addiction and implicates using pyrvinium as an autophagy inhibitor in combination with chemotherapeutic agents to improve their therapeutic efficacy.

Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy

We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (∼10 fold). It was also reported by others to have anti-tumor activity in vivo and selective toxicity against cancer cells under glucose starvation in vitro, but with unknown mechanism. Here, we provide evidence that pyrvinium suppresses the transcriptional activation of GRP78 and GRP94 induced by glucose deprivation or 2-deoxyglucose (2DG, a glycolysis inhibitor), but not by tunicamycin or A23187. Other UPR pathways induced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgene partially protected cells from pyrvinium induced cell death under glucose starvation, suggesting that suppression of the UPR is involved in pyrvinium mediated cytotoxicity under glucose starvation. Xenograft experiments showed rather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR.

Pyrvinium For The Treatment of Cancer

The present invention concerns a pyrvinium compound or an analog thereof for the treatment of cancers. This compound inhibits Wnt activity in the cells of cancers such as adrenocortical, hepatocellular, hepatoblastoma, malignant melanoma, ovarian, Wilm’s tumor, Barrett’s esophageal, glioma, bladder, breast, gastric, head & neck, lung cell, mesothelioma, and cervical cancers. The present invention also provides a method for assaying for compounds that alter Wnt pathway activity. Also provided are methods for treating Wnt-related non-cancer disease states.

Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I

Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially killcancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancertherapeutic potential. We therefore sought to characterize VCD’s anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD’s strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed.

Histone acetylation-mediated regulation of the Hippo pathway

WNT pathway inhibitor pyrvinium pamoate inhibits the self-renewal and metastasis of breast cancer stem cells

Acquisition of chemoresistance and metastatic phenotype are the major causes of breast cancer treatment failure and cancer-related mortality. Recently, a plethora of experimental and clinical studies points toward a central role of cancer stem cells (CSCs) in the chemoresistance and metastasis. In the present study, we demonstrated that pyrvinium pamoate (PP), an anthelmintic drug, inhibited proliferation of different subtypes of breast cancer cells (luminal: MCF-7, claudin-low: MDA-MB‑231, basal-like: MDA-MB‑468 and Her-2 enriched: SkBr-3) as a novel WNT pathway inhibitor. Additionally, PP was also shown to inhibit self-renewal of breast cancer stem cells (BCSCs) and decrease both CD44+CD24-/low and ALDH-positive BCSCs content in a panel of breast cancer cell lines. Besides, the metastatic potential and expression of EMT markers (such as N-cadherin, vimentin, Snail) were also found suppressed by PP. By using a xenograft model, we next tested the efficacy of PP on tumorigenicity of MDA-MB‑231, one of the most aggressive breast cancer cell lines, and we observed PP significantly delayed tumor growth in vivo. Moreover, in-depth analysis revealed that PP caused inhibition of WNT pathway activity and stemness regulator expression including NANOG, SOX2 and OCT4, which were inherently upregulated in the BCSCs as compared with the bulk of cells within the tumor. Collectively, our findings provide direct evidence for PP serving as a promising high-yield agent targeting BCSCs and cancer heterogeneity. Therefore, strategies combining PP with standard chemotherapy drugs which fail to eliminate the BCSCs hold promise to overcome BCSCs associated treatment resistance and achieve a better therapeutic outcome

Pyrvinium selectively induces apoptosis of lymphoma cells through impairing mitochondrial functions and JAK2/STAT5

Targeting mitochondrial respiration has emerged as an attractive therapeutic strategy in blood cancer due to their unique metabolic dependencies. In this study, we show that pyrvinium, a FDA-approved anthelmintic drug, selectively targets lymphoma T-cells though inhibition of mitochondrialfunctions and JAK2/STAT5. Pyrvinium induces apoptosis of malignant T-cell line Jurkat and primary T-cells from lymphoma patients while sparing T-cells from healthy donors. Increased level of active caspase-3 and decreased levels of Bcl-2 and Mcl-1 were also observed in Jurkat and lymphoma T-cells but not normal T-cells treated with pyrvinium. In addition, pyrvinium impairs mitochondrial functions by inhibit mitochondrial respiration, suppressing mitochondrial respiratory complex I activity, increasing ROS and decreasing ATP levels. However, the effects of pyrvinium were abolished in mitochondrial respiration-deficient Jurkat ρ(0) cells, confirming that pyrvinium acts on lymphoma T-cells via targeting mitochondrial respiration. We further show that lymphoma T-cells derived from patients depend more on mitochondrial respiration than normal T-cells, and this explains the selective toxicity of pyrvinium in lymphoma versus normal T-cells. Finally, we demonstrate that pyrvinium also suppresses JAK2/STAT5 signaling pathway in Jurkat cells. Our study suggests that pyrvinium is a useful addition to T-cell lymphoma treatment, and emphasizes the potential therapeutic value of the differences in the mitochondrial characteristics between malignant and normal T-cells in blood cancer.

Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.

The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells. Pyrvinium is effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells from TKI-resistant BP-CML patients, while cord blood CD34+ are largely unaffected. The effects of pyrvinium are further enhanced upon combination with dasatinib, a second generation BCR-ABL1 TKI. In a CML xenograft model pyrvinium significantly inhibitstumor growth as a single agent, with complete inhibition in combination with dasatinib. While pyrvinium has been shown to inhibit the Wnt/β-catenin signalling pathway via activation of casein kinase 1α , we find its activity in CML is not dependent on this pathway. Instead, we show that pyrvinium localizes to mitochondria and induces apoptosis by inhibiting mitochondrial respiration. Our study suggests that pyrvinium is a useful addition to the treatment armamentarium for BP-CML and that targeting mitochondrial respiration may be a potential therapeutic strategy in aggressive leukemia.

Pyrvinium Targets CD133 in Human Glioblastoma Brain Tumor-Initiating Cells.

Clonal evolution of cancer may be regulated by determinants of stemness, specifically self-renewal, and current therapies have not considered how genetic perturbations or properties of stemness affect such functional processes. Glioblastoma-initiating cells (GICs), identified by expression of the cell surface marker CD133, are shown to be chemoradioresistant. In the current study, we sought to elucidate the functional role of CD133 in self-renewal and identify compounds that can specifically target this CD133(+) treatment-refractory population.

Using gain/loss-of-function studies for CD133 we assessed the in vitro self-renewal and in vivo tumor formation capabilities of patient-derived glioblastoma cells. We generated a CD133 signature combined with an in silico screen to find compounds that target GICs. Self-renewal and proliferation assays on CD133-sorted samples were performed to identify the preferential action of hit compounds. In vivo efficacy of the lead compound pyrvinium was assessed in intracranial GIC xenografts and survival studies. Lastly, microarray analysis was performed on pyrvinium-treated GICs to discover core signaling events involved.

We discovered pyrvinium, a small-molecule inhibitor of GIC self-renewal in vitro and in vivo, in part through inhibition of Wnt/β-catenin signaling and other essential stem cell regulatory pathways. We provide a therapeutically tractable strategy to target self-renewing, chemoradioresistant, and functionally important CD133(+) stem cells that drive glioblastoma relapse and mortality.

Our study provides an integrated approach for the eradication of clonal populations responsible for cancer progression, and may apply to other aggressive and heterogeneous cancers. Clin Cancer Res; 21(23); 5324-37. ©2015 AACR.

Wnt blockers inhibit the proliferation of lung cancer stem cells.

Previous study has confirmed that the occurrence of Wnt pathway activation is associated with risk of non-small-cell lung cancerrecurrence. However, whether the pharmacologic blocking of the Wnt signaling pathway could provide therapeutic possibility remains unknown. The aim of the present study was to evaluate the therapeutic functions of the Wnt signaling pathway inhibitor pyrvinium pamoate (PP) on lung cancer stem cells (LCSCs) in vitro.

Colony formation and sphere culture were performed to enrich LCSCs from three lung cancer cell lines: PC9, SPC-A1, and A549. After confirming stemness by immunofluorescence, PP was employed for cell viability assay by comparison with three other kinds of Wnt signaling inhibitor: salinomycin, ICG-001, and silibinin. The effect of PP on LCSCs was further verified by colony formation assay and gene expression analysis.

LCSCs were successfully generated by sphere culture from SPC-A1 and PC9 cells, but not A549 cells. Immunofluorescence assay showed that LCSCs could express pluripotent stem cell markers, including NANOG, Oct4, KLF5, and SOX2, and Wnt signaling pathway molecules β-catenin and MYC. Half-maximal inhibitory concentrations of PP on SPC-A1, PC9, and A549 were 10 nM, 0.44 nM, and 0.21 nM, respectively, which are much lower than those of salinomycin, ICG-001, and silibinin. Moreover, significantly decreased colony formation and downregulation of pluripotent stem cell signaling pathway were observed in lung cancer cells after treatment with PP.

Wnt signaling inhibitor PP can inhibit proliferation of LCSCs, and the Wnt signaling pathway could be considered a promising therapeutic or interventional target in lung adenocarcinoma.

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.

Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancerstem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancerstem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancerstem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline,pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicatecancer stem cells was not yet appreciated.

The impact of pyrvinium pamoate on colon cancer cell viability.

The in vitro and in vivo effects of pyrvinium pamoate (PP), a newly identified WNT signaling inhibitor, were evaluated against colon cancercell lines and primary colon cancer samples.

Antiproliferative activity of PP and its effects on protein and RNA levels of WNT targets were evaluated on adenomatous polyposis coli (APC (mut)) and β-catenin(mut) cell lines, one WNT(wt) colon cancer cell line, as well as six primary colon cancer samples with mutant APC in vitro. In addition, the effect of PP on the growth of liver metastasis was examined.

PP blocked colon cancer cell growth in vitro in a dose-dependent manner with great differences in the inhibitory concentration (IC(50)), ranging from 0.6 × 10(-6) to 65 × 10(-6) mol/L for colon cancer cells with mutations in WNT signaling. In addition, PP demonstrated a cytotoxic effect on primary colon cancer samples. A combined cytotoxic effect of PP with 5-fluorouracil (5-FU) was observed for two cell lines. PP decreased messenger RNA (mRNA) and protein levels of known WNT target genes as c-MYC and thereby led to the induction of p21. PP inhibited the migration of HCT116 colon cancer cells in vitro and decreased tumor growth in vivo after intraportal injection of HCT116 cells in nude mice.

PP displays promising anticancer activity against a broad panel of human colon cancer cell lines, as well as primary colon cancersamples. However, our findings do not demonstrate a predominant cytotoxic effect of PP on colon cancer cells with mutations in WNT signaling.

Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium.

Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Furthermore, computational modeling predicts that pyrvinium binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants, which are thought to contribute to the growth of castration resistant prostate cancer (CRPC). PP also inhibits androgen-independent AR activation by HER2 kinase. The antiandrogen activity of pyrvinium manifests in the ability to inhibit the in vivo growth of CRPC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs) but not structurally unrelated transcription factors. PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density but does not affect lean body mass. Our results suggest that the noncompetitive AR inhibitor pyrvinium has significant potential to treat CRPC, including cancers driven by ligand-independent AR signaling.

The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer.

WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs). In this study, we used pyrvinium pamoate (PP), an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancercell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted.

Targeting the Wnt pathway in synovial sarcoma models.

Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents.

Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans.

Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells.

Activation of Wnt signalling due to inability to degrade β-catenin is found in >85% of colorectal cancers. Approximately half of colon cancers express a constitutively active KRAS protein. A significant fraction of patients show both abnormalities. We previously reported that simultaneous down-regulation of both β-catenin and KRAS was necessary to induce significant cell death and tumor growth inhibition of colorectal cancer cells. Although attractive, an RNAi-based therapeutic approach is still far from being employed in the clinical setting. Therefore, we sought to recapitulate our previous findings by the use of small-molecule inhibitors of β-catenin and KRAS. We show here that the β-catenin inhibitors PKF115-584 andpyrvinium pamoate block β-catenin-dependent transcriptional activity and synergize with the KRAS inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) in colon cancer cells driven by Wnt and KRAS oncogenic signals, but not in cells carrying BRAF mutations. The combined use of these compounds was superior to the use of any drug alone in inducing cell growth arrest, cell death, MYC and survivin down-modulation, and inhibition of anchorage-independent growth. Expression analysis of selected cancer-relevant genes revealed down-regulation of CD44 as a common response to the combined treatments. These data provide a proof of principle for a combination therapeutic strategy in colorectal cancer.

Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration

Pyrvinium pamoate (PP) is an FDA-approved classical anthelmintic, but is now attracting particular attention as an anti-cancer drug after recent findings of its potent cytotoxicity against various cancer cell lines only during glucose starvation, as well as its anti-tumor activity against hypovascularpancreatic cancer cells transplanted in mice. The molecular mechanisms by which PP promotes such preferential toxicity against cancer cells are currently under extensive investigation. PP suppressed the NADH-fumarate reductase system that mediates a reverse reaction of the mitochondrial electron-transport chain complex II in anaerobic organisms such as parasitic helminthes or mammalian cells under tumor microenvironment-mimicking hypoglycemic/hypoxic conditions, thereby inhibiting efficient ATP production. PP also inhibited the unfolded protein response induced by glucose starvation, thereby inhibiting the proliferation of pancreatic cancer cells. Even under normoglycemic/normoxic conditions, PP suppressed the mitochondrial electron-transport chain complex I and thereby STAT3, inhibiting the proliferation of myeloma/erythroleukemia cells. Here, we review accumulating knowledge on its working mechanisms and evaluate PP as a novel anti-cancer drug that targets mitochondrial respiration.

Repositioning approved drugs for the treatment of problematic cancers using a screening approach

Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan.


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33 thoughts on “Pyrvinium Pamoate: An Anti Worm Drug with Important Anti Cancer Potential

    1. Even if the absorption is low we may be able to protect at least the route through which PP is passing i.e. gastrointestinal route. Co administration of fat may help increase absorption. If needed for topical application I am thinking of mixing with DMSO.

  1. Thanks Daniel, we will try with whole milk or cream.Topical is not easy wife would never accept red tummy same about drinking PP in 50:50 alcohol+DMSO she would never touch it because of red teeth.Not sure about nebulizing PP suspension for inhalation it could give a result similar to inhalation of fine powder – irritated lungs and inflammations.
    PP is too promising to give up especially oral administration. Maybe if we could cover the red colour with something else or block its adhesion to teeth. Speculating about some dark chocolate drink – chocolate and women cannot go wrong.
    What would you suggest as start dosage if we presume that 100% of PP will be absorbed by the body?

  2. Hi Daniel, I’m giving up on PP solutions because when these react with some moisture precipitation starts in the same moment and solutions turn into suspensions. There is no way to avoid that during oral or IV administration. The real breakthrough is water soluble salts with high bio-availability as under “Other References” on this page: “Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy” There is a description under Materials and Methods/Compounds how to transfer PP to Pirvinium Phosphate.They have prepared Pirvinium Sulphate too and compared to PP, both Phosphate and Sulphate had higher efficacy than PP. Supporting Information/Figure S2. Pirvinium is the active moiety Pamoate doesn’t do thing. Maybe if we could manufacture Pirvinium Chloride it could be even better. One question remains, dosage.Kidney and liver toxicity cannot be excluded.

    1. Hi Paul, now I am on holiday but when I get the time I will check the paragraph you mentioned. I agree, it is too good to give it up so fast. Otherwise I would use PP only for the places that it can be “touched” by it, like gastro intestinal, blader, etc tumors and tumors at the surface of the body where the DMSO composition may be applied.

      We are also using cycles of PP from time to time to try prevent occurrence of tumors in the path mentioned above.

  3. Dear D, I do have a general question that I wanted to ask for a long time, and I was actually discussing it with Emad a few days ago;
    why do you think some people respond to simple treatments so well yet others, with the exact same diagnosis, do many things and still fail? for an instance, someone takes 200 mg of Mebendazole as solo therapy and almost goes into remission in 4 weeks and yet another patient with an strong protocol addressing lots of escape roots doesn’t achieve much, or many other similar instances that you know better.

    1. Hi Pouya,

      this is of course a very good but also a very difficult question.

      Assuming that if you take tumor cells from both patients (the one responding and the other not) and for both cases there will be a response in the laboratory, I can only explain the difference in response as depending on how much of the drug can actually reach the tumor cells. This in turn can depend on tumor location, its physical structure and the tumor vessels, next to the dynamics of the specific drug in various people from its bio availability (the fraction of an administered dose of unchanged drug that reaches the systemic circulation) to the pharmacokinetics (how an organism affects a drug).

      To me, this means that when we use a treatment we should try to address as many of those above:
      – tumor location – how to deliver the drug to reach the tumor (for example, if the tumor is in the brain we should use approaches that would open up BBB, if the tumor is in the lungs we should think of inhalations)
      – physical structure – around the tumors can be fibroblasts that may need to be addressed first, and even more important, if the tumor is e.g. in the lungs but not only is possible that parasites have developed around the tumor that would first interact with the drug before reaching the tumor – some doctors suggest using Ivermectin prior to the main treatment
      – tumor vessels – may be of very bed shape as they grow very fast and it may be difficult to get through for the drugs – so we need to use some approaches to open up the vessels prior to the treatment (like coffee, Niacin, Quercetin, Nitroglycerine)
      – bio availability – for example Mebendazole is very poorly absorbed in the body. taking it with some fat will help increase its absorption. Other approach to overcome this barrier is IV as it is done for Vitamin C to get to high dose required for potential anti cancer effects since the oral administration leads to about 5% only absorption
      – pharmacokinetics – for example Cimetidine when taken at the same time with Mebendazole increases the maximum serum concentration of mebendazole by inhibiting an enzyme at the liver that would otherwise take care faster of eliminating mebendazole out of the body.

      Now lets, assume that we took care of all the above and that enough drug is approaching the tumor:

      – pH: Like we discussed here around the tumors there is a lot of acidity (protons) ready to interact with anything that is willing to interact with them which is the case of drugs that are bases. Depending on the tumor size and other elements, some tumors may have more acidity compared to others. If the anti cancer drug is a base (wich is the case for many of the chemos) it will be annihilated before reaching the tumor. This is why as we discussed on thsi website, it make sens to reduce acidity prior to chemo. But not only chemo. For example chloroquine which has strong anti cancer potential may not reach the tumor at all due to the acidity around the tumor

      – MDR: than let’s say that the drug succeed to get through and reach inside the cancer cell. As we know tumors (some more and some less) have the pumps that can push the drugs out. This is something that we said we want to address with e.g. Verapamil

      – Antioxidants: and like we discussed some tumor cells can fight better than others ROS that is produced by various anti cancer substances. This is why we thought of addressing that with Paracetamol and others.

      Many of the above have been discussed here

      The point is that all these aspects can be different in different people that may have same type of tumors. This in turn can lead to difference in response.

      It may sound complicated when we brake it down into so many possibilities but actually it is not that complicated and we should be happy we are aware of them and the fact that we know ways to address these kind of potential resistance mechanisms.

      I hope this answers a bit your question. This is off-course a purely logical and scientific response to your question.
      I think beyond all the chemicals and scientific logic, the human mind holds response we are not yet aware of and I think the mindset and the expectation and believe of the patient may count even more than the above.

      Kind regards,

      1. thank you so much for the elaborate response Danie, as a Hypochondriac myself,I have dealt with the negative power of mind for a long time so I can only imagine how strong it’s healing properties can be if one can harness that power.. years ago, when I heard about a family friend who had a severe case of Multiple Sclerosis, I was convinced I too am going to contact the disease. in a matter of a month, my body started showing all the symptoms of MS. not even an MRI was able to help me get rid of those symptoms. if it was not because of Luvox I probably was bed ridden now.
        also, thanks for the very informative linkage; am reading and learning.

    1. Hi Liliana,

      I am not aware of anyone using pyrvinium with syn sarcoma. The challenge with pyrvinium is its absorption in the body, but for the tumors that can be accessed directly by pyrvinium, it is expected to be very relevant.
      For Syn Sarcoma, as I understand, one of the major pathways to target is Wnt/β-catenin In order to increase the effectiveness of targeting this pathway, next to Pyrvinium I would use several other inhibitors such as Niclosamidide, Ivermectin, Metformin, Celecoxib and if possible Salinomycin. Here is a nice article showing a summary of drugs targeting Wnt/β-catenin

      I hope this helps.

      Would be great if you could contribute to some of the discussions here whenever you find the time, given your extensive experience in oncology. Thanks in advance for that.

      Kind regards,

  4. Thank you Daniel for your reply and suggestions.
    I started from Mario Capecchi, from University of Utah and Noble Prize, is one of the co-author. Something -not exactly defined – induces me to prefer pyrvinium to the other drugs you cited. I suppose that metformin interfering with IGF-related pathways and celecoxib with other mechanisms could be generically useful in anticancer therapy. However, I feel that there is not compelling interest by companies in studying anthelmintics as anticancer agents.

    1. Thank you Liliana. I didn’t know one of the authors of the paper I cited (M. Capecchi) actually won Nobel Prize … I just read his story here
      The contribution of a Nobel Prize winner to this paper adds even more weight to the concept. Indeed, metformin and celecoxib have other off target actions that are leading to their intensively studied anti cancer effects.

      When I was referring to the list above, I was thinking more of a drug cocktail approach, adding to pyrvinium some the other drugs to target various steps in the WNT pathway and increase the chance for effectiveness. That should be possible given their relatively low toxicity.

      Indeed anthelmintics are very relevant drugs when it comes to cancer. Mebendazole is one of the most interesting to me, due to the combination of potential and low toxicity. It is actually a microtubule dynamics inhibitor. Same is the antifungal Griseofulvine researched by German and Danish research groups, Unfortunately, they are not covered by patents anymore and as a result no company will be interested to invest – due to this they will remain confined in academic space, unless oncologist will start using them off label next to conventional treatments. So much valuable work is done in academic environment and remains there due to similar reasons.

      I am actually considering that, through the Foundations, I should create a platform to inform oncologist regarding the opportunities that come with the re purposed drugs. I will check if I can access EU funds for that purpose. What do you think? Would this be a good idea?

        1. Hi Paul, there are so many … I discussed about some that I found most interesting and plan to discuss others that are very interesting. There is nowhere a consolidate list – the info is now fragmented – see also comment of Meech.

  5. Yes Daniel, I think it could be the right way. Perhaps, it would be useful to join multiple competences – genetists, pharmacologists, medical oncologists, etc.- in a panel which could suggest the best medications for each tumors based on pivotal pathway.

    1. Yes, this is a good idea. Thank you for the suggestion, Liliana.
      From your earlier comments, I understand you are currently considering anthelmintics as a relevant class of drugs to fight cancer. Are you looking at those as complementary or alternative to conventional options?

  6. My husband has a synovial sarcoma metastatic to the lung. I started third line of therapy, however, I do not have much faith in the actual treatment based on current behaviour of tumor. As I usually did, I searched the best treatment options without blinkers. Pyrvinium could be an interesting option given the interference with wnt pathway, however, pharmakokinetics limits its potential use. I am wondering whether other administration routes could be supposed, but I can discuss these questions only here.

    1. Dear Liliana, I am sorry to hear you have to deal with this challenge. I will see if I find something else relevant but until then you may want to carefully study the literature on Salinomycin. It is a substance known to interfere with WNT That is also one of the reason we decided to use it as WNT is very relevant in Adrenal Cancer as well, and we saw the most intense anticancer response to it. We did use the IV route for it.

  7. Dear Daniel, my husband died on June this year. I would like to ask for your cooperation in a small editorial project. I could explain it by e-mail, but I have not your address. Thank you in advance. Liliana

    1. Dear Liliana, I am so sorry to hear that … Please accept my deepest condolences Liliana. My e-mail address is listed here I am connected with other oncologist around the world starting up various projects and will be my pleasure to consider a collaboration with you on this line, as well as possibly connecting you with the others if you like. I will wait for your e-mail.
      Kind regards,

  8. I was reading this again and just noticed the reference here ” Pyrvinium targets autophagy addiction to promote cancer cell death (Ref.)” is lost, in case you needed to fix it dear D.

  9. Hi Daniel

    Great post! You mentioned: “Yet, taken orally maybe very relevant to all forms of cancers that can easily be reached in that way, i.e. gastric, colon, colorectal, blader and possibly hepatocellular.”

    In your mind, would PP only work in these (above mentioned) cancers? Or in all cancers, given that it is a mitochondrial inhibitor. I’m also aware of Lisanti’s research and he always mentions in his papers that PP can eradicate CSC because it’s a mitochondrial inhibitor. So as far as I can tell, he seems to be thinking that it works in any kind of cancer, if I understand correctly?

    Do you think it’s even worth trying? I’m treating a cancer in my knee (Giant cell tumor of the tendon sheath). I was also thinking about topical administration, but it’s very hard to get PP in larger quantities, unless if you order from Alibaba… What are your thoughts on these issues?

    Thanks for everything you do! Best,

    1. Hi Alen,

      Thank you! In my view PP is one of the top repurposed drugs in terms of anti cancer potential, connected with multiple anti-cancer mechanisms including WNT inhibition. Due to the mechanisms addressed, PP is relevant to most cancer types. So I very much resontate with Lisanti (and I appreciate his research). I only mentioned the gastro intestinal ones because of it’s poor bio-availability. But if we could find a way to deliver it directly to the tumor that would be one good way to overcome the bio-availability.

      In this case I would only try topical or make it liposomal and consider injection under the skin to create a local depot. I would try to get it from western chemical suppliers first. If not, Chinese suppliers could also be an option but it has to be tested when received to make sure it is what it has been ordered.

      Kind regards,

  10. Hello Daniel,

    I believe I have throat cancer of some type(which I believe it is esophageal cancer). I recently noticed symptoms getting worse and realized this wasn’t ‘just ordinary symptoms from GERD’ that I am used to having. I am in the process of getting a doctor appointment as soon as possible.

    It looks like Pyrvinium might be a good option assuming the tumor in my throat is on the surface and able to come in contact with drug. Does that sound accurate? I imagine I would crush the pill and drinking slowly to try and get the throat coated with as much Pyrvinium as possible.

    I am in the US and will look for a place to purchase this product. I haven’t been able to explore the website much yet but read there were some online pharmacies listed.

    Very impressed with the website and all the information presented. Thank You!

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