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Atovacuona , Azitromicina , Babesiosis , Humanos , Atovacuona/uso terapéutico , Atovacuona/efectos adversos , Babesiosis/tratamiento farmacológico , Azitromicina/uso terapéutico , Azitromicina/efectos adversos , Azitromicina/administración & dosificación , Fluorenos/uso terapéutico , Fluorenos/efectos adversos , Fluorenos/administración & dosificación , Quimioterapia Combinada , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Resultado del Tratamiento , Hospitalización , AminoquinolinasRESUMEN
Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per µL of blood (p/µL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/µL. However, at follow-up, parasite density increased to 7,630 p/µL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.
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Antimaláricos , Atovacuona , Malaria Falciparum , Plasmodium falciparum , Proguanil , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/diagnóstico , Ghana , Antimaláricos/uso terapéutico , Persona de Mediana Edad , Masculino , Plasmodium falciparum/aislamiento & purificación , Proguanil/uso terapéutico , Atovacuona/uso terapéutico , Viaje , Artemisininas/uso terapéutico , Artesunato/uso terapéutico , Parasitemia/tratamiento farmacológico , Parasitemia/diagnóstico , Doxiciclina/uso terapéutico , Combinación de Medicamentos , Insuficiencia del Tratamiento , Combinación Arteméter y Lumefantrina/uso terapéuticoRESUMEN
Endochin-like quinolones (ELQs) define a class of small molecule antimicrobials that target the mitochondrial electron transport chain of various human parasites by inhibiting their cytochrome bc1 complexes. The compounds have shown potent activity against a wide range of protozoan parasites, including the intraerythrocytic parasites Plasmodium and Babesia, the agents of human malaria and babesiosis, respectively. First-generation ELQ compounds were previously found to reduce infection by Babesia microti and Babesia duncani in animal models of human babesiosis but achieved a radical cure only in combination with atovaquone and required further optimization to address pharmacological limitations. Here, we report the identification of two second-generation 3-biaryl ELQ compounds, ELQ-596 and ELQ-650, with potent antibabesial activity in vitro and favorable pharmacological properties. In particular, ELQ-598, a prodrug of ELQ-596, demonstrated high efficacy as an orally administered monotherapy at 10 mg/kg. The compound achieved radical cure in both the chronic model of B. microti-induced babesiosis in immunocompromised mice and the lethal infection model induced by B. duncani in immunocompetent mice. Given its high potency, favorable physicochemical properties, and low toxicity profile, ELQ-596 represents a promising drug for the treatment of human babesiosis.
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Babesiosis , Quinolonas , Ratones , Humanos , Animales , Babesiosis/tratamiento farmacológico , Babesiosis/parasitología , Quinolonas/farmacología , Atovacuona/farmacología , Atovacuona/uso terapéuticoRESUMEN
BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone. OBJECTIVES: To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis. METHODS: DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023. STUDY ELIGIBILITY CRITERIA: Comparative randomized controlled trials (RCTs). PARTICIPANTS: PWH. INTERVENTIONS: Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo. ASSESSMENT OF RISK OF BIAS: Cochrane risk-of-bias tool for RCTs 2. METHODS OF DATA SYNTHESIS: Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed. RESULTS: A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups. CONCLUSIONS: TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
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Infecciones por VIH , Metaanálisis en Red , Pneumocystis carinii , Neumonía por Pneumocystis , Ensayos Clínicos Controlados Aleatorios como Asunto , Combinación Trimetoprim y Sulfametoxazol , Humanos , Neumonía por Pneumocystis/prevención & control , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Combinación Trimetoprim y Sulfametoxazol/administración & dosificación , Combinación Trimetoprim y Sulfametoxazol/efectos adversos , Pneumocystis carinii/efectos de los fármacos , Infecciones por VIH/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/prevención & control , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Dapsona/uso terapéutico , Dapsona/efectos adversos , Dapsona/administración & dosificación , Pentamidina/uso terapéutico , Pentamidina/administración & dosificación , Pentamidina/efectos adversos , Atovacuona/uso terapéutico , Atovacuona/efectos adversos , Antifúngicos/uso terapéutico , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Resultado del TratamientoRESUMEN
HISTORY: A 42-year-old female presented with a two-day history of vomiting, diarrhea, fever and chills. Two weeks before she had returned to Germany from a Safari in Tanzania. She had disregarded the recommendation to take antimalarial chemoprophylaxis. CLINICAL FINDINGS AND DIAGNOSIS: The thin blood film showed Plasmodium falciparum-parasitized erythrocytes, and Plasmodium falciparum malaria was diagnosed. The full blood count showed thrombocytopenia and ultrasound imaging revealed splenomegaly. Initially the criteria for complicated malaria were not fulfilled. THERAPY AND COURSE: We started oral therapy with atovaquone/proguanil. The patient vomited the tablets twice. Therefore therapy was switched to intravenous artesunate. Subsequently, parasitemia dropped from 2.8 to 1.0â% within 22 hours. After 3 days of artesunate i.âv., treatment could then be completed with oral atovaquone/proguanil, and the symptoms resolved. CONCLUSIONS: Patients with malaria and persistent vomiting should be treated intravenously and monitored closely, as severe gastrointestinal symptoms may reflect impending organ failure. We therefore propose including persistent vomiting in the list of criteria for complicated malaria.
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Antimaláricos , Malaria Falciparum , Malaria , Femenino , Humanos , Adulto , Proguanil/uso terapéutico , Atovacuona/uso terapéutico , Artesunato/uso terapéutico , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Malaria Falciparum/complicaciones , Malaria Falciparum/diagnóstico , Malaria Falciparum/tratamiento farmacológico , Combinación de Medicamentos , Vómitos/etiologíaRESUMEN
Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer.
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Antineoplásicos , Nanopartículas , Neoplasias Ováricas , Humanos , Femenino , Ratones , Animales , Paclitaxel , Neoplasias Ováricas/patología , Atovacuona/farmacología , Atovacuona/uso terapéutico , Quercetina/farmacología , Quercetina/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Resistencia a Múltiples Medicamentos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Metabolismo Energético , Adenosina Trifosfato/metabolismoRESUMEN
Abnormal activation of the Wnt/ß-catenin signaling pathway is a driving force behind the progression of gastric cancer. Atovaquone, known as an antimalarial drug, has emerged as a potential candidate for anti-cancer therapy. This study investigated atovaquone's effects on gastric cancer and its underlying mechanisms. Using gastric cancer cell lines, we found that atovaquone, at concentrations relevant to clinical use, significantly reduced their viability. Notably, atovaquone exhibited a lower effectiveness in reducing the viability of normal gastric cells compared to gastric cancer cells. We further demonstrated that atovaquone inhibited gastric cancer growth and colony formation. Mechanism studies revealed that atovaquone inhibited mitochondrial respiration and induced oxidative stress. Experiments using ρ0 cells, deficient in mitochondrial respiration, indicated a slightly weaker effect of atovaquone on inducing apoptosis compared to wildtype cells. Atovaquone increased phosphorylated ß-catenin at Ser45 and Ser33/37/Thr41, elevated Axin, and reduced ß-catenin. The inhibitory effects of atovaquone on ß-catenin were reversed upon depletion of CK1α. Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer.
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Neoplasias Gástricas , Vía de Señalización Wnt , Animales , Ratones , Atovacuona/farmacología , Atovacuona/uso terapéutico , beta Catenina/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Línea Celular Tumoral , Caseína Quinasas/metabolismo , Proliferación CelularRESUMEN
T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune evasion resulting in poor therapeutic efficacy. The introduction of ferroptosis-targeted inducers offers a potential solution, as they empower T cells to induce ferroptosis and exert influence over the tumor microenvironment. Atovaquone (ATO) stands as a prospective pharmaceutical candidate with the potential to target ferroptosis, effectively provoking an excessive generation and accumulation of reactive oxygen species (ROS). In this study, we evaluated the effectiveness of a combination therapy comprising ATO and TCR-T cells against hepatocellular carcinoma (HCC), both in vitro and in vivo. The results of lactate dehydrogenase and cytokine assays demonstrated that ATO enhanced cytotoxicity mediated by AFP-specific TCR-T cells and promoted the release of IFN-γ in vitro. Additionally, in an established HCC xenograft mouse model, the combined therapy with low-dose ATO and TCR-T cells exhibited heightened efficacy in suppressing tumor growth, with no apparent adverse effects, comparable to the results achieved through monotherapy. The RNA-seq data unveiled a significant activation of the ferroptosis-related pathway in the combination therapy group in comparison to the TCR-T cells group. Mechanistically, the synergy between ATO and TCR-T cells augmented the release of IFN-γ by TCR-T cells, while concurrently elevating the intracellular and mitochondrial levels of ROS, expanding the labile iron pool, and impairing the integrity of the mitochondrial membrane in HepG2 cells. This multifaceted interaction culminated in the potentiation of ferroptosis within the tumor, primarily induced by an excess of ROS. In summary, the co-administration of ATO and TCR-T cells in HCC exhibited heightened vulnerability to ferroptosis. This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/terapia , Atovacuona/farmacología , Atovacuona/uso terapéutico , Especies Reactivas de Oxígeno , Estudios Prospectivos , Neoplasias Hepáticas/terapia , Receptores de Antígenos de Linfocitos T , Modelos Animales de Enfermedad , Microambiente TumoralRESUMEN
Canine babesiosis has been increasingly diagnosed in various regions of Germany such as north-eastern Germany in recent years. A dog with several relapses of Babesia canis infection after treatment with imidocarb is described. A 9-year-old male Magyar Viszla with B. canis infection was referred after two treatments with imidocarb (dosage 2.1 mg/kg SC) because of lethargy, fever and pancytopenia (additional treatments with prednisolone and doxycycline). Merozoites were detected in the blood smear and imidocarb treatment was repeated. Clinical signs, pancytopenia and a positive B. canis PCR occurred after the 3rd (6 mg/kg SC), 4th (7.7 mg/kg SC) and 5th (7.5 mg/kg SC and doxycycline for 4 weeks in addition) imidocarb injection and thorough tick prevention with isoxazoline and permethrin products. 12 days after the 5th injection, the PCR was negative for the first time. The dog was again presented with fever 35 days after the 5th injection. The B. canis PCR was positive and laboratory examination revealed pancytopenia. Treatment with atovaquone/azithromycin for 18 days was performed and no further relapse occurred for 32 weeks. In the case of suspected imidocarb resistance in B. canis infection, treatment with atovaquone/azithromycin can be an alternative.
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Antiprotozoarios , Babesia , Babesiosis , Enfermedades de los Perros , Pancitopenia , Masculino , Perros , Animales , Imidocarbo/uso terapéutico , Antiprotozoarios/uso terapéutico , Atovacuona/farmacología , Atovacuona/uso terapéutico , Doxiciclina/uso terapéutico , Azitromicina/uso terapéutico , Pancitopenia/tratamiento farmacológico , Babesiosis/tratamiento farmacológico , Babesiosis/epidemiología , Babesiosis/diagnóstico , Alemania/epidemiología , Insuficiencia del Tratamiento , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/diagnósticoRESUMEN
Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.
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Complejo III de Transporte de Electrones , Neoplasias , Humanos , Animales , Ratones , Atovacuona/farmacología , Atovacuona/uso terapéutico , Neoplasias/tratamiento farmacológico , Linfocitos T CD8-positivos , Inmunoterapia/métodos , Antígeno B7-H1 , Microambiente TumoralRESUMEN
Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights the need for new and more effective treatments. Here we demonstrate that the 8-aminoquinoline antimalarial drug tafenoquine inhibits the growth of different Babesia species in vitro, is highly effective against Babesia microti and Babesia duncani in mice and protects animals from lethal infection caused by atovaquone-sensitive and -resistant B. duncani strains. We further show that a combination of tafenoquine and atovaquone achieves cure with no recrudescence in both models of human babesiosis. Interestingly, elimination of B. duncani infection in animals following drug treatment also confers immunity to subsequent challenge. Altogether, the data demonstrate superior efficacy of tafenoquine plus atovaquone combination over current therapies for the treatment of human babesiosis and highlight its potential in providing protective immunity against Babesia following parasite clearance.
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Aminoquinolinas , Babesia , Babesiosis , Humanos , Animales , Ratones , Atovacuona/farmacología , Atovacuona/uso terapéutico , Modelos TeóricosRESUMEN
The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly understood. In our previous studies, we highlighted the association between isoprenylcysteine carboxylmethyltransferase (ICMT) and chemoresistance in NPC. In this current research, we revealed that both 5-FU and cisplatin-resistant NPC cells exhibited elevated mitochondrial function and increased expression of mitochondrial genes, independent of ICMT. Our investigations further showed that classic mitochondrial inhibitors, such as oligomycin, antimycin, and rotenone, were notably more effective in reducing viability in chemo-resistant NPC cells compared to parental cells. Moreover, we identified two antimicrobial drugs, tigecycline and atovaquone, recognized as mitochondrial inhibitors, as potent agents for decreasing chemo-resistant NPC cells by targeting mitochondrial respiration. Remarkably, tigecycline and atovaquone, administered at tolerable doses, inhibited chemo-resistant NPC growth in mouse models and extended overall survival rates. This work unveils the efficacy of mitochondrial inhibition as a promising strategy to overcome chemo-resistance in NPC. Additionally, our findings highlight the potential repurposing of clinically available drugs like tigecycline and atovaquone for treating NPC patients who develop chemoresistance.
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Resistencia a Antineoplásicos , Neoplasias Nasofaríngeas , Animales , Ratones , Humanos , Carcinoma Nasofaríngeo/metabolismo , Atovacuona/farmacología , Atovacuona/uso terapéutico , Tigeciclina/farmacología , Tigeciclina/uso terapéutico , Línea Celular Tumoral , Cisplatino/farmacología , Mitocondrias , Neoplasias Nasofaríngeas/metabolismoRESUMEN
IMPORTANCE: This study is the first of its kind that suggests exosomes as a nano-carrier loaded with atovaquone (ATQ), which could be considered as a new strategy for improving the effectiveness of ATQ against acute and chronic phases of Toxoplasma gondii.
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Exosomas , Toxoplasma , Atovacuona/farmacología , Atovacuona/uso terapéutico , MacrófagosRESUMEN
Canine babesiosis is an important protozoan tick-borne disease associated with anemia and thrombocytopenia and caused by several different Babesia spp. Babesia negevi was first reported to infect dogs in the Middle East in 2020. This study describes the presentation, clinical signs, parasitemia levels quantified by molecular techniques, laboratory findings and treatment of dogs infected with B. negevi following the first description of this species. Clinical findings in the infected dogs, a 3-year old female and two 8-week old male and female pups, included extreme lethargy and pale mucous membranes, anemia and thrombocytopenia found in all three animals. Fever was present in the older female and icterus in the female pup. Babesia parasites resembling B. negevi were detected by microscopy of blood smears from the dogs. PCR of blood targeting the 18S rRNA and cox1 genes confirmed that babesiosis was caused by B. negevi and PCR targeting the Borrelia flagellin gene indicated co-infection with Borrelia persica in two dogs. Treatment of the dogs with imidocarb dipropionate resulted in clinical improvement and initial decrease in the B. negevi parasite load as detected by quantitative PCR in two dogs, however the female pup continued to deteriorate and died. The parasite load in the 3-year old female decreased from 43,451 parasites/µl blood pre-imidocarb dipropionate treatment to 803 parasites/µl within two weeks. In the surviving pup, it decreased from 3,293,538 parasites/µl pre-treatment to 20,092 parasites/µl after two weeks. Babesia negevi DNA was still recovered from blood samples by PCR despite repeated treatment with imidocarb dipropionate one-month post-treatment in the surviving pup and up to seven months post-treatment in the 3-year old female. Only treatment with atovaquone and azithromycin for ten days eliminated B. negevi in both dogs as confirmed by negative PCR two weeks later. In conclusion, treatment with imidocarb dipropionate was helpful for recovery from clinical disease but did not facilitate parasite elimination, and it is therefore recommended to treat canine B. negevi infection with the combination of atovaquone and azithromycin.
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Anemia , Antiprotozoarios , Babesia , Babesiosis , Enfermedades de los Perros , Trombocitopenia , Perros , Animales , Masculino , Femenino , Babesiosis/parasitología , Atovacuona/uso terapéutico , Antiprotozoarios/uso terapéutico , Azitromicina/uso terapéutico , Babesia/genética , Anemia/tratamiento farmacológico , Enfermedades de los Perros/parasitologíaRESUMEN
Diminazene aceturate (DA), imidocarb dipropionate (ID), atovaquone (ATO), azithromycin (AZI), clindamycin, and quinine have been used to treat animal and human babesiosis for many years, despite their negative effects and rising indications of resistance. Thus, finding anti-babesial compounds that can either treat the infection or lower the dose of drugs given has been a primary objective. Quinazolines are one of the most important nitrogen heterocycles, with a wide range of pharmacological activities including analgesic, anti-inflammatory, sedative-hypnotic, anti-histaminic, anti-cancer, and anti-protozoan properties. The present study investigated the anti-babesial activities of twenty 6,7-dimethoxyquinazoline-2,4-diamines on Babesia spp. One candidate, 6,7-dimethoxy-N4-ethylisopropyl-N2-ethyl(pyridin-4-yl)quinazoline-2,4-diamine (SHG02), showed potent inhibition on Babesia gibsoni in vitro, as well as on B. microti and B. rodhaini in mice. Our findings indicate that the candidate compound SHG02 is promising for further development of anti-babesial drugs and provides a new structure to be explored for developing anti-Babesia therapeutics.
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Antiprotozoarios , Babesia , Babesiosis , Enfermedades de los Perros , Perros , Animales , Humanos , Ratones , Atovacuona/farmacología , Atovacuona/uso terapéutico , Azitromicina/farmacología , Azitromicina/uso terapéutico , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéuticoRESUMEN
BACKGROUND: Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are also the primary factors leading to death in colon cancer patients. Atovaquone is an antimalarial drug, and its anticancer effect has recently been demonstrated in several cancer models in vitro and in vivo, but it has not been examined in the treatment of colorectal cancer. METHODS: To elucidate the effect of atovaquone on colorectal cancer. We used RNA transcriptome sequencing, RTâPCR and Western blot experiments to examine the expression of NF-κB (p-P65), EMT-related proteins and related inflammatory factors (IL1B, IL6, CCL20, CCL2, CXCL8, CXCL6, IL6ST, FAS, IL10 and IL1A). The effect of atovaquone on colorectal cancer metastasis was validated using an animal model of lung metastases. We further used transcriptome sequencing, the GCBI bioinformatics database and the STRING database to predict relevant target proteins. Furthermore, pathological sections were collected from relevant cases for immunohistochemical verification. RESULTS: This study showed that atovaquone could inhibit colorectal cancer metastasis and invasion in vivo and in vitro, inhibit the expression of E-cadherin protein, and promote the protein expression of N-cadherin, vimentin, ZEB1, Snail and Slug. Atovaquone could inhibit EMT by inhibiting NF-κB (p-P65) and related inflammatory factors. Further bioinformatics analysis and verification showed that PDGFRß was one of the targets of atovaquone. CONCLUSION: In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRß, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.
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Neoplasias Colorrectales , FN-kappa B , Animales , Humanos , FN-kappa B/metabolismo , Atovacuona/farmacología , Atovacuona/uso terapéutico , Línea Celular Tumoral , Transducción de Señal , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal , Movimiento CelularRESUMEN
The opportunistic apicomplexan parasite Toxoplasma gondii is the etiologic agent for toxoplasmosis, which can infect a widespread range of hosts, particularly humans and warm-blooded animals. The present chemotherapy to treat or prevent toxoplasmosis is deficient and is based on diverse drugs such as atovaquone, trimethoprim, spiramycine, which are effective in acute toxoplasmosis. Therefore, a safe chemotherapy is required for toxoplasmosis considering that its responsible agent, T. gondii, provokes severe illness and death in pregnant women and immunodeficient patients. A certain disadvantage of the available treatments is the lack of effectiveness against the tissue cyst of the parasite. A safe chemotherapy to combat toxoplasmosis should be based on the metabolic differences between the parasite and the mammalian host. This article covers different relevant molecular targets to combat this disease including the isoprenoid pathway (farnesyl diphosphate synthase, squalene synthase), dihydrofolate reductase, calcium-dependent protein kinases, histone deacetylase, mitochondrial electron transport chain, etc.
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Toxoplasma , Toxoplasmosis , Animales , Humanos , Femenino , Embarazo , Toxoplasmosis/tratamiento farmacológico , Atovacuona/metabolismo , Atovacuona/farmacología , Atovacuona/uso terapéutico , Trimetoprim/farmacología , MamíferosRESUMEN
Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field.
Asunto(s)
Anopheles , Antimaláricos , Malaria Falciparum , Malaria , Parásitos , Vacunas , Humanos , Animales , Ratones , Atovacuona/farmacología , Atovacuona/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Malaria/parasitología , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/genética , Anopheles/parasitología , Antiparasitarios/uso terapéuticoRESUMEN
Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA-approved drug for treatment of Pneumocystis carinii pneumonia and malaria. Patent US2023017373 describe the use of mito-atovaquone for the treatment of several types of cancer. Mito-atovaquone demonstrated antiproliferative activity in cell lines of pancreatic cancer, lung cancer and brain cancer and inhibited tumor growth in syngeneic mouse models and in animals genetically prone to breast cancer. Mito-atovaquone has the potential to be used successfully in the treatment of various types of tumors.