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Expert Opinion on Therapeutic Targets 2023Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity.... (Review)
Review
INTRODUCTION
Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy.
AREAS COVERED
Triphenylphosphonium cation (TPP)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies.
EXPERT OPINION
TPP-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP-based OXPHOS-inhibiting drugs in cancer prevention and treatment.
Topics: Humans; Mice; Animals; Mitochondria; Oxidative Phosphorylation; Neoplasms; Drug Delivery Systems; Antineoplastic Agents
PubMed: 37736880
DOI: 10.1080/14728222.2023.2261631 -
BMC Cancer Nov 2023Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are...
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, RT‒PCR 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 PDGFRβ 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-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.
Topics: Animals; Humans; NF-kappa B; Atovaquone; Cell Line, Tumor; Signal Transduction; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Cell Movement
PubMed: 37932661
DOI: 10.1186/s12885-023-11585-9 -
European Journal of Medicinal Chemistry Dec 2023The opportunistic apicomplexan parasite Toxoplasma gondii is the etiologic agent for toxoplasmosis, which can infect a widespread range of hosts, particularly humans and... (Review)
Review
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.
Topics: Animals; Humans; Female; Pregnancy; Toxoplasma; Toxoplasmosis; Atovaquone; Trimethoprim; Mammals
PubMed: 37871407
DOI: 10.1016/j.ejmech.2023.115885 -
Pharmaceutical Patent Analyst Jul 2023Repurposing 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...
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 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.
Topics: Mice; Animals; Atovaquone; Drug Repositioning; Antifungal Agents; Naphthoquinones; Pneumonia, Pneumocystis; Neoplasms; Mitomycin
PubMed: 37801038
DOI: 10.4155/ppa-2023-0015 -
Medical Mycology Sep 2023Pneumocystis jirovecii is a transmissible fungus responsible for severe pneumonia (Pneumocystis pneumonia [PCP]) in immunocompromised patients. Missense mutations due to... (Review)
Review
Pneumocystis jirovecii is a transmissible fungus responsible for severe pneumonia (Pneumocystis pneumonia [PCP]) in immunocompromised patients. Missense mutations due to atovaquone selective pressure have been identified on cytochrome b (CYB) gene of P. jirovecii. It was recently shown that atovaquone prophylaxis can lead to the selection of specific P. jirovecii CYB mutants potentially resistant to atovaquone among organ transplant recipients. In this context, our objectives were to provide data on P. jirovecii CYB mutants and the putative selective pressure exerted by atovaquone on P. jirovecii organisms in France. A total of 123 patients (124 P. jirovecii specimens) from four metropolitan hospitals and two overseas hospitals were retrospectively enrolled. Fourteen patients had prior exposure to atovaquone, whereas 109 patients did not at the time of P. jirovecii detection. A 638 base-pair fragment of the CYB gene of P. jirovecii was amplified and sequenced. A total of 10 single nucleotide polymorphisms (SNPs) were identified. Both missense mutations C431T (Ala144Val) and C823T (Leu275Phe), located at the Qo active site of the enzyme, were significantly associated with prior atovaquone exposure, these mutations being conversely incidental in the absence of prior atovaquone exposure (P < 0.001). Considering that the aforementioned hospitals may be representative of the national territory, these findings suggest that the overall presence of P. jirovecii CYB mutants remains low in France.
Topics: Animals; Pneumocystis carinii; Atovaquone; Cytochromes b; Retrospective Studies; Mutation
PubMed: 37656874
DOI: 10.1093/mmy/myad095 -
Nature Communications Oct 2023Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However,...
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.
Topics: Humans; Animals; Mice; Atovaquone; Parasites; Antimalarials; Malaria; Malaria, Falciparum; Plasmodium falciparum; Anopheles; Antiparasitic Agents; Vaccines
PubMed: 37828012
DOI: 10.1038/s41467-023-42030-x -
Clinical Infectious Diseases : An... May 2024Relapsing babesiosis often occurs in highly immunocompromised patients and has been attributed to the acquisition of resistance against drugs commonly used for treatment...
BACKGROUND
Relapsing babesiosis often occurs in highly immunocompromised patients and has been attributed to the acquisition of resistance against drugs commonly used for treatment such as atovaquone, azithromycin, and clindamycin. Tafenoquine, which is approved for malaria prophylaxis and presumptive antirelapse treatment of Plasmodium vivax malaria, has shown activity against Babesia microti in several animal models of acute infection and in a single human case of relapsing babesiosis. Here, we report 5 cases of relapsing babesiosis treated with tafenoquine, including the previous case, and begin to define the conditions for optimal use of tafenoquine in relapsing babesiosis.
METHODS
A definitive diagnosis of babesiosis was made by microscopic examination of Giemsa-stained thin blood smears or a real-time polymerase chain reaction (PCR) that targets the parasite 18S rRNA gene. Clearance of B. microti infection was ascertained by use of blood smear and real-time PCR.
RESULTS
Tafenoquine was initiated with a loading dose of 600 mg. A weekly maintenance dose consisted of 200 mg or 300 mg; the lower dose was associated with a delayed clearance of B. microti. In 2 cases, all antimicrobial agents but tafenoquine were discontinued prior to clearance of infection. In 2 other cases, clearance was achieved while tafenoquine was administered along with other antimicrobial agents. In 3 of these 4 cases, tafenoquine was used in combination with atovaquone-proguanil. Other agents included atovaquone, azithromycin, and/or clindamycin. In 1 case, tafenoquine was administered alone and failed to prevent relapse.
CONCLUSIONS
Tafenoquine can be a useful adjunct for the treatment of highly immunocompromised patients experiencing relapsing babesiosis caused by B. microti.
PubMed: 38814096
DOI: 10.1093/cid/ciae238 -
The Journal of Infectious Diseases Aug 2023Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects...
BACKGROUND
Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.
METHODS
We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.
RESULTS
Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations.
CONCLUSIONS
These data suggest that atovaquone would be a potential candidate for treating mpox.
Topics: Humans; Atovaquone; Mefloquine; Monkeypox virus
PubMed: 36892247
DOI: 10.1093/infdis/jiad058 -
Biomaterials Mar 2024Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair...
Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair abilities of cancer cells. Mitochondria, as the pivotal player in ferroptosis, exhibit tremendous therapeutic potential by targeting the intramitochondrial anti-ferroptotic pathway mediated by dihydroorotate dehydrogenase (DHODH). In this study, an albumin-based nanomedicine was developed to induce augmented ferroptosis in triple-negative breast cancer (TNBC) by depleting glutathione (GSH) and inhibiting DHODH activity. The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). SRF is an FDA-approved ferroptosis inducer and ATO is the only drug used in clinical that targets mitochondria. By combining the effects of SRF and ATO, ATO/SRF@BSA promoted the accumulation of lipid peroxides within mitochondria by inhibiting the glutathione peroxidase 4 (GPX4)-GSH pathway and downregulating the DHODH-coenzyme Q (CoQH) defense mechanism, triggers a burst of lipid peroxides. Simultaneously, ATO/SRF@BSA suppressed cancer cell self-repair and enhanced cell death by inhibiting the synthesis of adenosine triphosphate (ATP) and pyrimidine nucleotides. Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.
Topics: Humans; Dihydroorotate Dehydrogenase; Triple Negative Breast Neoplasms; Ferroptosis; Lipid Peroxides; Serum Albumin, Bovine; Atovaquone; Glutathione; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38154441
DOI: 10.1016/j.biomaterials.2023.122447 -
Frontiers in Pharmacology 2023
PubMed: 37767402
DOI: 10.3389/fphar.2023.1282233