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Blood Cancer Journal Jun 2020Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains...
Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
Topics: Animals; Anthelmintics; Antineoplastic Agents; Apoptosis; Drug Repositioning; Drug Resistance, Neoplasm; Humans; Mice, SCID; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 32591499
DOI: 10.1038/s41408-020-0339-9 -
International Journal For Parasitology.... Aug 2023Reports of anthelmintic resistance in Ancylostoma caninum are increasing in frequency in the United States of America (USA). In the last few years in vitro and in vivo... (Review)
Review
Reports of anthelmintic resistance in Ancylostoma caninum are increasing in frequency in the United States of America (USA). In the last few years in vitro and in vivo studies characterized individual isolates, demonstrating multiple anthelmintic drug resistance (MADR). In 2021, the American Association of Veterinary Parasitologists initiated a hookworm task force to address this issue. The first report of drug resistant A. caninum occurred in 1987 in Australian racing Greyhounds. In the last five years multiple case reports and investigations show drug resistant A. caninum is becoming a much greater problem in the USA and now extends beyond racing Greyhounds into the general companion animal dog population. The literature, regarding drug resistance in livestock and equine nematodes, provides helpful guidance along with diagnostic methods to better understand the evolution and selection of canine MADR hookworms; however, there are limitations and caveats due to A. caninum's unique biology and zoonotic potential. Mass drug administration (MDA) of anthelminthic drugs to humans to reduce morbidity associated with human hookworms (Necator americanus) should consider the factors that contributed to the development of MADR A. caninum. Finally, as Greyhound racing undergoes termination in some regions and the retired dogs undergo subsequent rehoming, drug resistant parasites, if present, are carried with them. Drug resistant A. caninum requires greater recognition by the veterinary community, and small animal practitioners need to be aware of the spread into current pet dog populations. The current understanding of anthelmintic resistance, available treatments, and environmental mitigation for these drug resistant A. caninum isolates must be monitored for horizontal spread. A major goal in this emerging problem is to prevent continued dissemination.
Topics: Animals; Dogs; Horses; Humans; Ancylostoma; Ancylostomiasis; Dog Diseases; Australia; Anthelmintics; Ancylostomatoidea
PubMed: 37229949
DOI: 10.1016/j.ijpddr.2023.04.003 -
International Journal For Parasitology.... Dec 2020Infections by parasitic nematodes inflict a huge burden on the health of humans and livestock throughout the world. Anthelmintic drugs are the first line of defense...
Infections by parasitic nematodes inflict a huge burden on the health of humans and livestock throughout the world. Anthelmintic drugs are the first line of defense against these infections. Unfortunately, resistance to these drugs is rampant and continues to spread. To improve treatment strategies, we must understand the genetics and molecular mechanisms that underlie resistance. Studies of the fungus Aspergillus nidulans and the free-living nematode Caenorhabditis elegans discovered that a beta-tubulin gene is mutated in benzimidazole (BZ) resistant strains. In parasitic nematode populations, three beta-tubulin alleles, F167Y, E198A, and F200Y, have long been correlated with resistance. Additionally, improvements in sequencing technologies have identified new alleles - E198V, E198L, E198K, E198I, and E198Stop - also correlated with BZ resistance. However, none of these alleles have been proven to cause resistance. To empirically demonstrate this point, we independently introduced the F167Y, E198A, and F200Y alleles as well as two of the newly identified alleles, E198V and E198L, into the BZ susceptible C. elegans N2 genetic background using the CRISPR-Cas9 system. These genome-edited strains were exposed to both albendazole and fenbendazole to quantitatively measure animal responses to BZs. We used a range of concentrations for each BZ compound to define response curves and found that all five of the alleles conferred resistance to BZ compounds equal to a loss of the entire beta-tubulin gene. These results prove that the parasite beta-tubulin alleles cause resistance. The E198V allele is found at low frequencies along with the E198L allele in natural parasite populations, suggesting that it could affect fitness. We performed competitive fitness assays and demonstrated that the E198V allele reduces animal health, supporting the hypothesis that this allele might be less fit in field populations. Overall, we present a powerful platform to quantitatively assess anthelmintic resistance and effects of specific resistance alleles on organismal fitness in the presence or absence of the drug.
Topics: Alleles; Animals; Anthelmintics; Benzimidazoles; Caenorhabditis elegans; Drug Resistance; Humans; Tubulin
PubMed: 32858477
DOI: 10.1016/j.ijpddr.2020.08.003 -
International Journal For Parasitology.... Apr 2022Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In... (Review)
Review
Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In nematodes, the physiological behaviors including locomotion, navigation, feeding and reproduction, are regulated by these protein entities. Majority of the antinematodal chemotherapeutics target the ion channels to disrupt essential biological functions. Here, we have summarized current advances in our understanding of nematode ion channel pharmacology. We review cys-loop ligand gated ion channels (LGICs), including nicotinic acetylcholine receptors (nAChRs), acetylcholine-chloride gated ion channels (ACCs), glutamate-gated chloride channels (GluCls), and GABA (γ-aminobutyric acid) receptors, and other ionotropic receptors (transient receptor potential (TRP) channels and potassium ion channels). We have provided an update on the pharmacological properties of these channels from various nematodes. This article catalogs the differences in ion channel composition and resulting pharmacology in the phylum Nematoda. This diversity in ion channel subunit repertoire and pharmacology emphasizes the importance of pursuing species-specific drug target research. In this review, we have provided an overview of recent advances in techniques and functional assays available for screening ion channel properties and their application.
Topics: Acetylcholine; Animals; Anthelmintics; Nematoda; Receptors, GABA; Receptors, Nicotinic
PubMed: 35149380
DOI: 10.1016/j.ijpddr.2021.12.001 -
Veterinary Parasitology Feb 2022In the majority of mixed or sequential gazing studies with sheep, cattle performance remained unaffected. However, the treatment regime of the sheep in these studies was...
In the majority of mixed or sequential gazing studies with sheep, cattle performance remained unaffected. However, the treatment regime of the sheep in these studies was often intense and this may have limited cross-transmission of nematodes from sheep to cattle. We conducted a sequential grazing trial with cattle and sheep with moderate anthelmintic intervention. Twenty first season grazing steers were stratified to 10 couples according to their origin, egg excretion per gram faeces (EPG), metabolic weight and previous weight gain record. Thirty naturally infected ewe lambs were stratified to 5 groups according to metabolic live weight and EPG. Five pairs of the steers were sequentially grazed with the 5 groups of lambs whereas another five pairs of steers served as control. Grazing duration was 70 days with a subsequent indoor period of additional 35 days for the steers. Weight and EPG was recorded 3 days before and 27, 49, 70 and 105 days after trial start. The recorded live-weight of the sequentially grazed steers was 182 ± 14, 191 ± 11, 205 ± 15, 219 ± 15 and 236 ± 18 and the live-weight of the control steers was 180 ± 18, 193 ± 19, 203 ± 21, 217 ± 24 and 234 ± 24 kg respectively. The EPG of the sequentially grazed steers 3 days before grazing start and at day 27, 49, 70 and 105 was 94 ± 100, 95 ± 48, 49 ± 42, 58 ± 41 and 140 ± 73 EPG respectively. The EPG of the control steers at the same dates was 96 ± 82, 98 ± 24, 104 ± 77, 98 ± 71 and 270 ± 287 EPG respectively. The sequentially grazed steer groups did not differ from the control groups with regard to EPG, live weight and daily weight gain. However, the sequentially grazed steers showed elevated pepsinogen levels compared to the control steers (e.g. 3.34 ± 1.05 units tyrosine and 1.29 ± 0.50 units tyrosine after 70 days of grazing, respectively). Larval samples from individual steer coprocultures of both groups were tested PCR-positive for Cooperia oncophora, Ostertagia ostertagi and Haemonchus contortus. We conclude that short term sequential grazing of first season grazing steers with lambs excreting mainly eggs of Haemonchus spp. did not adversely affect steer performance despite increased pepsinogen values. However, hot and dry conditions may have had a suppressive effect on larval development, migration and finally uptake by the steers.
Topics: Animals; Anthelmintics; Cattle; Feces; Female; Haemonchus; Nematoda; Ovum; Parasite Egg Count; Sheep
PubMed: 35030350
DOI: 10.1016/j.vetpar.2021.109645 -
European Journal of Medicinal Chemistry May 2018The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC = 19.1 μM)...
The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC = 19.1 μM) and Fasciola hepatica (IC = 17.7 μM), two related parasitic blood and liver flukes responsible for the neglected tropical diseases schistosomiasis and fascioliasis, respectively. Here, we aimed to increase the potency of 7-keto-sempervirol by total synthesis of 30 structural analogues. Subsequent screening of these new diterpenoids against juvenile and adult lifecycle stages of both parasites as well as the human HepG2 liver cell line and the bovine MDBK kidney cell line revealed structure-activity relationship trends. The most active analogue, 7d, displayed improved dual anthelmintic activity over 7-keto-sempervirol (IC ≈ 6 μM for larval blood flukes; IC ≈ 3 μM for juvenile liver flukes) and moderate selectivity (SI ≈ 4-5 for blood flukes, 8-13 for liver flukes compared to HepG2 and MDBK cells, respectively). Phenotypic studies using scanning electron microscopy revealed substantial tegumental alterations in both helminth species, supporting the hypothesis that the parasite surface is one of the main targets of this family of molecules. Further modifications of 7d could lead to greater potency and selectivity metrics resulting in a new class of broad-spectrum anthelmintic.
Topics: Animals; Anthelmintics; Cattle; Cell Line; Diterpenes; Dose-Response Relationship, Drug; Drug Design; Fasciola hepatica; Hep G2 Cells; Humans; Molecular Structure; Parasitic Sensitivity Tests; Schistosoma mansoni; Structure-Activity Relationship
PubMed: 29698860
DOI: 10.1016/j.ejmech.2018.04.032 -
Parasites & Vectors Nov 2023Alveolar echinococcosis (AE) is a lethal zoonosis caused by the fox tapeworm Echinococcus multilocularis. The disease is difficult to treat, and an effective therapeutic...
BACKGROUND
Alveolar echinococcosis (AE) is a lethal zoonosis caused by the fox tapeworm Echinococcus multilocularis. The disease is difficult to treat, and an effective therapeutic drug is urgently needed. Echinococcus multilocularis-associated angiogenesis is required by the parasite for growth and metastasis; however, whether antiangiogenic therapy is effective for treating AE is unclear.
METHODS
The in vivo efficacy of sunitinib malate (SU11248) was evaluated in mice by secondary infection with E. multilocularis. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate treatment effects on serum IL-4 and vascular endothelial growth factor A (VEGFA) levels after SU11248 treatment. Gross morphological observations and immunohistochemical staining were used to evaluate the impact of SU11248 on angiogenesis and the expression of pro-angiogenic factors VEGFA and VEGF receptor 2 (VEGFR2) in the metacestode tissues. Furthermore, the anthelmintic effects of SU11248 were tested on E. multilocularis metacestodes in vitro. The effect of SU11248 on the expression of VEGFA, VEGFR2, and phosphorylated VEGFR2 (p-VEGFR2) in liver cells infected with protoscoleces in vitro was detected by western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The influence of SU11248 on endothelial progenitor cell (EPC) proliferation and migration was determined using CCK8 and transwell assays.
RESULTS
In vivo, SU11248 treatment markedly reduced neovascular lesion formation and substantially inhibited E. multilocularis metacestode growth in mice. Further, it exhibited high anti-hydatid activity as efficiently as albendazole (ABZ), and the treatment resulted in reduced protoscolex development. In addition, VEGFA, VEGFR2, and p-VEGFR2 expression was significantly decreased in the metacestode tissues after SU11248 treatment. However, no effect of SU11248 on serum IL-4 levels was observed. In vitro, SU11248 exhibited some anthelmintic effects and damaged the cellular structure in the germinal layer of metacestodes at concentrations below those generally considered acceptable for treatment (0.12-0.5 μM). Western blotting, RT-qPCR, and ELISA showed that in co-cultured systems, only p-VEGFR2 levels tended to decrease with increasing SU11248 concentrations. Furthermore, SU11248 was less toxic to Reuber rat hepatoma (RH) cells and metacestodes than to EPCs, and 0.1 μM SU11248 completely inhibited EPC migration to the supernatants of liver cell and protoscolex co-cultures.
CONCLUSIONS
SU11248 is a potential candidate drug for the treatment of AE, which predominantly inhibits parasite-induced angiogenesis. Host-targeted anti-angiogenesis treatment strategies constitute a new avenue for the treatment of AE.
Topics: Mice; Animals; Echinococcus multilocularis; Sunitinib; Vascular Endothelial Growth Factor A; Interleukin-4; Anthelmintics
PubMed: 37936208
DOI: 10.1186/s13071-023-05999-4 -
Brazilian Journal of Biology = Revista... 2022The current study was designed to check the anthelmintic activities of some local plants. Seeds of Amomum (A.) subulatum and Vitex (V.) negundo in different solvents...
The current study was designed to check the anthelmintic activities of some local plants. Seeds of Amomum (A.) subulatum and Vitex (V.) negundo in different solvents were subjected to in vitro (adult motility assay; AMA and egg hatch assay; EHA) and in vivo (faecal egg count reduction test; FECRT) anthelmintic activity testing protocols using Haemonchus (H.) contortus as an experimental model. The results of AMA, EHA, and FECRT were statistically analysed through linear regression and Duncan multiple range test. In AMA test, at 50 mg mL-1 concentration, the percent mortality of H. contortus was higher in A. subulatum than V. negundo, whereas, in EHA test, A. subulatum was proven better ovicidal (LC50=14.2 µg mL-1) than V. negundo (LC50= 65.7405 µg mL-1). The FECRT also indicated the better efficacy of A. subulatum than V. negundo against natural infection of gastrointestinal (GI) parasites. The crude powder of plants used in this study showed 29.6% to 57.7% anthelmintic. The reduction rate was found higher for A. subulatum (3 g kg-1) as compared to V. negundo (7 g kg-1). Reagrding efficacy analysis of solvents used for plants extract, ethyl acetate and chloroform were found better in increasing ovicidal activity in adult worms (in vitro testing), whereas, the crude aqueous methanol was found better than the crude powders in in vivo testing. It will be beneficial to document the indigenous knowledge to standard scientific procedures for their validation. This study will help to motivate the farmers to make a better choice of cultivation of the indigenous plants because of their varying efficacies as an alternative preventive approach against the GI parasitic infections.
Topics: Amomum; Anthelmintics; Plant Extracts; Seeds; Solvents; Vitex
PubMed: 35674590
DOI: 10.1590/1519-6984.261768 -
International Journal For Parasitology.... Aug 2023Ancylostoma caninum is the most common and important gastrointestinal nematode of dogs in the United States. Despite recent reports of A. caninum isolates resistant to...
Ancylostoma caninum is the most common and important gastrointestinal nematode of dogs in the United States. Despite recent reports of A. caninum isolates resistant to all classes of anthelmintics, little is known about the frequency and extent of this anthelmintic resistance. The study aim was to evaluate the efficacy of three commercial anthelmintic products in the treatment of foxhound dogs with a history of persistent A. caninum infections. In the first phase of this study, 35 foxhounds were randomly divided into three treatment groups: moxidectin/imidacloprid (MI), pyrantel pamoate/febantel/praziquantel (PFP), and emodepside/praziquantel (EP). Fecal samples were collected on day 0, 11, and 33 post-treatment (PT), and hookworm eggs were quantified using the mini-FLOTAC technique with a multiplication factor of 5 eggs per gram (EPG). The fecal egg count reduction (FECR) on day 11 PT was 65% (95% CI: 62%-68%) for MI, 69% (95% CI: 66%-72%) for PFP, and 96% (95% CI: 94%-97%) for EP. On day 33 PT, the FEC in the MI and PFP groups returned to almost the same values as on day 0, while in the EP group, the FEC remained low. Since MI and PFP proved ineffective, 32 animals were randomly divided into two groups in the second phase. They were treated either with a combination of MI/PFP or EP. The FECR at day 13 PT for the combination MI/PFP was 89% (95% CI: 87%-91%) and 99% (95% CI: 98%-99%) for EP. These results suggest that this A. caninum population is resistant to multiple anthelmintics. Although the combination of MI/PFP improved the anthelmintic efficacy, the FECR remained below 90%. Future studies are indicated to evaluate further the epidemiology of persistent hookworm infections in dogs in the US and to identify more effective treatment protocols as they pose a significant health risk to canine and human health.
Topics: Animals; Dogs; Ancylostoma; Ancylostomatoidea; Anthelmintics; Dog Diseases; Feces; Hookworm Infections; Nematoda; Parasite Egg Count; Praziquantel
PubMed: 37481894
DOI: 10.1016/j.ijpddr.2023.07.001 -
BMC Veterinary Research May 2024As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but...
As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but also shows anti-cancer effects against several types of cancer, exhibits anti-cancer effects in paclitaxel and doxorubicin-resistant cancer cells. However, fenbendazole's poor in water solubility (0.3 µg/mL), limits its clinical applications. Even great efforts were made toward increasing its water solubility, the results were not significant to reach anti-cancer drug delivery requirement (5-10 mg/mL). Through single factor and orthogonal strategy, many complex conditions were designed and used to prepare the complexes, the inclusion complex with methyl-β-cyclodextrin with 29.2 % of inclusion rate and 89.5% of inclusion yield can increase drug's water solubility to 20.21 mg/mL, which is the best result so far. Its structure was confirmed by differential scanning calorimetry, scanning electron microscopic image, 1D and 2D NMR spectra in DO. In its in vitro pharmacokinetic study, fenbendazole was 75% released in 15 min., in its in vivo pharmacokinetic study, the bio-availabilities of fenbendazole, its major metabolic anthelmintic agent oxfendazole and its minor metabolic anthelmintic agent oxfendazole were increased to 138%, 149% and 169% respectively, which would allow for fewer drug doses to achieve the same therapeutic effect and suggest that the complex can be used as a potential anticancer agent.
Topics: Fenbendazole; Animals; beta-Cyclodextrins; Solubility; Antineoplastic Agents; Male; Anthelmintics
PubMed: 38769544
DOI: 10.1186/s12917-024-04056-1