-
BMC Medicine Nov 2022Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and...
BACKGROUND
Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking.
METHODS
By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS
A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62-0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81).
CONCLUSIONS
This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.
Topics: Adult; Humans; Proguanil; Atovaquone; Cohort Studies; Drug Combinations; Antimalarials; Colorectal Neoplasms; Malaria, Falciparum
PubMed: 36357883
DOI: 10.1186/s12916-022-02643-3 -
Journal of Travel Medicine 2014
Review
Topics: Antimalarials; Atovaquone; Chemoprevention; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Proguanil; Time Factors
PubMed: 24593022
DOI: 10.1111/jtm.12100 -
Current Drug Delivery 2020The present study reports the use of MicrofluidizerTM technology to form a stable nanosuspension of atovaquone (ATQ) using quality by design (QbD) approach.
OBJECTIVE
The present study reports the use of MicrofluidizerTM technology to form a stable nanosuspension of atovaquone (ATQ) using quality by design (QbD) approach.
METHODS
The patient-centric quality target product profile and critical quality attributes (CQAs) were identified. A Box-Behnken design was employed for the optimization of dependent variables, while CQAs like particle size and PDI were evaluated as response variables. Effective optimization of ATQ nanosuspension preparation using Microfluidizer processor as a novel green technology was achieved using QbD approach.
RESULT
The prepared nanosuspension had a mean particle size of 865 nm ± 5%, PDI of 0.261 ± 3%, and zeta potential of -1.79 ± 5 mV. The characterization of the prepared nanosuspension by SEM, DSC, and XRD revealed its nano-crystalline nature whereas FTIR spectroscopic analysis confirmed the absence of any physicochemical interaction because of process parameters between the drug and excipients.
CONCLUSION
In vitro dissolution studies of the nanosuspension using USP-IV exhibited a 100% cumulative drug release over 90 minutes, which is significantly better than that of ATQ pure API. In vivo pharmacokinetic studies revealed bioequivalence of ATQ nanosuspensions by Microfluidizer homogenization process to the marketed formulation1.
Topics: Animals; Anti-Infective Agents; Atovaquone; Biological Availability; Drug Design; Drug Liberation; Male; Nanoparticles; Particle Size; Rats, Sprague-Dawley; Solubility; Suspensions; Wettability
PubMed: 31880260
DOI: 10.2174/1567201817666191227095019 -
The Journal of Infectious Diseases Jan 2024Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights...
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.
Topics: Humans; Animals; Mice; Babesiosis; Atovaquone; Babesia; Models, Theoretical; Aminoquinolines
PubMed: 38169301
DOI: 10.1093/infdis/jiad315 -
Journal of Travel Medicine Jul 2022
Topics: Antimalarials; Atovaquone; Drug Combinations; Healthy Volunteers; Humans; Ketoconazole; Malaria, Falciparum; Proguanil
PubMed: 35532299
DOI: 10.1093/jtm/taac058 -
Journal of Bioenergetics and... Aug 2018The clinical management of anaplastic thyroid carcinoma and follicular thyroid carcinoma is challenging and requires an alternative therapeutic strategy. Although...
The clinical management of anaplastic thyroid carcinoma and follicular thyroid carcinoma is challenging and requires an alternative therapeutic strategy. Although atovaquone is an FDA-approved anti-malarial drug, studies has recently demonstrated its anti-cancer activities. In line with these efforts, our study shows that atovaquone is an attractive candidate for thyroid cancer treatment. We show that atovaquone significantly inhibits growth, migration and survival in a concentration-dependent manner in 8505C and FTC113 cells. Mechanistically, atovaquone inhibits mitochondrial complex III activity, leading to mitochondrial respiration inhibition and reduction of ATP production in thyroid cancer cells. The inhibitory effects of atovaquone is reversed in mitochondrial respiration-deficient 8505C ρ0 cells, confirming mitochondrial respiration as the mechanism of atovaquone's action in thyroid cancer. In addition, atovaquone suppresses phosphorylation of STAT3 in thyroid cancer wildype but not ρ0 cells, demonstrating that STAT3 phosphorylation inhibition by atovaquone is a consequence of mitochondrial respiration inhibition. Notably, we further demonstrate that atovaquone significantly augments doxorubicin's inhibitory effects via suppressing mitochondrial respiration and STAT3. Our findings suggest that atovaquone can be repurposed for thyroid cancer treatment. Our work also highlights that targeting mitochondrial respiration may represent potential therapeutic strategy in thyroid cancer.
Topics: Atovaquone; Cell Line; Cell Line, Tumor; Cell Respiration; Cell Survival; Doxorubicin; Drug Synergism; Humans; Mitochondria; Phosphorylation; STAT3 Transcription Factor; Thyroid Neoplasms
PubMed: 29687367
DOI: 10.1007/s10863-018-9755-y -
Experimental Parasitology Oct 2022Atovaquone (ATV) has a growth inhibitory effect against Babesia gibsoni. The target site is considered mitochondria, as in the case of Plasmodium spp.; ATV would...
Atovaquone (ATV) has a growth inhibitory effect against Babesia gibsoni. The target site is considered mitochondria, as in the case of Plasmodium spp.; ATV would collapse the mitochondrial membrane potential. B. gibsoni has also reported that single nucleotide polymorphisms in cytochrome b of mitochondria are involved in ATV susceptibility. However, the details are still unknown. The study aim was to measure the mitochondrial membrane potential of B. gibsoni and evaluate the effect of ATV alone and combined with proguanil (PG) on the mitochondrial membrane potential. As a result of exposure of wild-type B. gibsoni to ATV alone, the number of cells with decreased mitochondrial membrane potential increased. When wild-type B. gibsoni was exposed to the ATV + PG combination, the peak value of mitochondrial membrane potential was larger than that when exposed to ATV alone. It was suggested that ATV alone affects the mitochondrial membrane potential of B. gibsoni, and the effect is enhanced by the combination of ATV and PG. The effect of ATV was weakened for B. gibsoni having reduced sensitivity to ATV (B. gibsoni with M121I), and the effect was not enhanced by the combination of ATV and PG. Although we still need to elucidate the mechanism of ATV and PG for B. gibsoni, these results strongly suggests that the target of ATV for B. gibsoni is also cytochrome b of mitochondria.
Topics: Animals; Atovaquone; Babesiosis; Cytochromes b; Dog Diseases; Dogs; Membrane Potential, Mitochondrial
PubMed: 36027930
DOI: 10.1016/j.exppara.2022.108354 -
Revista Brasileira de Parasitologia... 2021Neospora caninum is an apicomplexan parasite that causes abortion in cattle, resulting in significant economic losses. There is no commercial treatment for neosporosis,...
Neospora caninum is an apicomplexan parasite that causes abortion in cattle, resulting in significant economic losses. There is no commercial treatment for neosporosis, and drug repositioning is a fast strategy to test possible candidates against N. caninum. In this article, we describe the effects of atovaquone, chloroquine, quinine, primaquine and tetracycline on N. caninum proliferation. The IC50 concentrations in N. caninum were compared to the current information based on previous studies for Plasmodium and Toxoplasma gondii, correlating to the described mechanisms of action of each tested drug. The inhibitory patterns indicate similarities and differences among N. caninum, Plasmodium and T. gondii. For example, atovaquone demonstrates high antiparasitic activity in all the analyzed models, while chloroquine does not inhibit N. caninum. On the other hand, tetracycline is effective against Plasmodium and N. caninum, despite its low activity in T. gondii models. The repurposing of antimalarial drugs in N. caninum is a fast and inexpensive way to develop novel formulations using well-established compounds.
Topics: Antimalarials; Atovaquone; Chloroquine; Neospora; Primaquine; Quinine; Tetracyclines
PubMed: 33787719
DOI: 10.1590/S1984-29612021006 -
Trends in Parasitology Oct 2007Atovaquone is a substituted hydroxynaphthoquinone that is used therapeutically for treating Plasmodium falciparum malaria, Pneumocystis jirovecii pneumonia and... (Review)
Review
Atovaquone is a substituted hydroxynaphthoquinone that is used therapeutically for treating Plasmodium falciparum malaria, Pneumocystis jirovecii pneumonia and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting parasite and fungal respiration by binding to the cytochrome bc1 complex. The recent, growing failure of atovaquone treatment and increased mortality of patients with malaria or Pneumocystis pneumonia has been linked to the appearance of mutations in the cytochrome b gene. To better understand the molecular basis of drug resistance, we have developed the yeast and bovine bc1 complexes as surrogates to model the molecular interaction of atovaquone with human and resistant pathogen enzymes.
Topics: Amino Acid Sequence; Animals; Anti-Infective Agents; Atovaquone; Electron Transport Complex III; Enzyme Inhibitors; Humans; Malaria, Falciparum; Models, Molecular; Molecular Sequence Data; Plasmodium falciparum; Pneumocystis carinii; Pneumonia, Pneumocystis; Sequence Alignment; Toxoplasma; Toxoplasmosis; Yeasts
PubMed: 17826334
DOI: 10.1016/j.pt.2007.08.004 -
Cancer Immunology, Immunotherapy : CII Feb 2024T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune...
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.
Topics: Humans; Animals; Mice; Carcinoma, Hepatocellular; Atovaquone; Reactive Oxygen Species; Ferroptosis; Prospective Studies; Liver Neoplasms; Receptors, Antigen, T-Cell; Disease Models, Animal; Tumor Microenvironment
PubMed: 38349553
DOI: 10.1007/s00262-024-03628-2