Quambalarine B, a Secondary Metabolite from <i>Quambalaria cyanescens</i> with Potential Anticancer Properties

Grobárová, Valéria; Vališ, Karel; Talacko, Pavel; Pavlů, Barbora; Hernychová, Lucie; Nováková, J.; Stodůlková, Eva; Flieger, Miroslav; Novák, Petr; Černý, Jan

doi:10.1021/acs.jnatprod.6b00362

Cited by 9 publications

(9 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a potential result of high AMP levels, we confirmed a decrease in O-glycosylation of proteins, which was represented as an important regulator of stability of several oncogenic factors such as C-MYC. Consistent with this hypothesis, C-MYC levels were significantly downregulated during QB treatment [ 24 ]. Hence, inhibition of hexosamine pathway and protein O-glycosylation provided a new possibility to regulate leukemia cells proliferation [ 41 ].…”

Section: Discussionmentioning

confidence: 64%

“…On the other hand, serine represents one of the end-point glycolysis-derived metabolites and allosterically activates PKM2 activity [ 34 ]. We have previously demonstrated that QB treatment decreases C-MYC protein levels and PKM2 mRNA levels in several leukemic cells [ 24 ]. In this study, we also demonstrated an increase in the serine levels after QB treatment; hence, we tested PKM activity after QB treatment using enzymatic assay.…”

Section: Resultsmentioning

confidence: 99%

“…As the activity of these complexes is tightly linked to other metabolic pathways, we tracked alterations in these pathways during treatment of leukemic cells with IC 50 concentration of QB as determined by MTS assay. The treatment showed the inhibitory effect on cellular proliferation, did not induce cell death and led to the rearrangement of metabolism of Jurkat cells [ 24 ]. Inhibition of ETC by QB led to increased levels of intracellular AMP, which inhibited anabolic pathways crucial for leukemic cells proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…QB effectively blocks proliferation of several leukemic cell lines and induces loss of proton gradient across the inner mitochondrial membrane [ 23 ]. QB also inhibits expression of C-MYC oncoprotein and attenuates mTOR signaling in several tested leukemic cell lines [ 24 ]. Since QB possesses substituted C2 and C3 positions in its structure, we presume redox cycling together with target oxidoreductases interference as a key mechanism responsible for QB anti-cancer activity.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B

et al. 2017

Self Cite

View full text Add to dashboard Cite

Abnormalities in cancer metabolism represent potential targets for cancer therapy. We have recently identified a natural compound Quambalarine B (QB), which inhibits proliferation of several leukemic cell lines followed by cell death. We have predicted ubiquinone binding sites of mitochondrial respiratory complexes as potential molecular targets of QB in leukemia cells. Hence, we tracked the effect of QB on leukemia metabolism by applying several omics and biochemical techniques. We have confirmed the inhibition of respiratory complexes by QB and found an increase in the intracellular AMP levels together with respiratory substrates. Inhibition of mitochondrial respiration by QB triggered reprogramming of leukemic cell metabolism involving disproportions in glycolytic flux, inhibition of proteins O-glycosylation, stimulation of glycine synthesis pathway, and pyruvate kinase activity, followed by an increase in pyruvate and a decrease in lactate levels. Inhibition of mitochondrial complex I by QB suppressed folate metabolism as determined by a decrease in formate production. We have also observed an increase in cellular levels of several amino acids except for aspartate, indicating the dependence of Jurkat (T-ALL) cells on aspartate synthesis. These results indicate blockade of mitochondrial complex I and II activity by QB and reduction in aspartate and folate metabolism as therapeutic targets in T-ALL cells. Anti-cancer activity of QB was also confirmed during in vivo studies, suggesting the therapeutic potential of this natural compound.

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…This led to increased pyruvic acid and decreased lactic acid levels. To inhibit mitochondrial complex I activity, quambalarine B inhibits folic Quambalarine B ( 57) is a natural naphthoquinonic compound from Quambalariac yanescens [115]. It inhibited the activity of mitochondrial complex I and II and reduced the metabolism of aspartic acid and folic acid as therapeutic targets in Jurkat cells.…”

Section: Quinonesmentioning

confidence: 99%

Natural Products Targeting the Mitochondria in Cancers

Yang

Zhang

et al. 2020

Molecules

View full text Add to dashboard Cite

There are abundant sources of anticancer drugs in nature that have a broad prospect in anticancer drug discovery. Natural compounds, with biological activities extracted from plants and marine and microbial metabolites, have significant antitumor effects, but their mechanisms are various. In addition to providing energy to cells, mitochondria are involved in processes, such as cell differentiation, cell signaling, and cell apoptosis, and they have the ability to regulate cell growth and cell cycle. Summing up recent data on how natural products regulate mitochondria is valuable for the development of anticancer drugs. This review focuses on natural products that have shown antitumor effects via regulating mitochondria. The search was done in PubMed, Web of Science, and Google Scholar databases, over a 5-year period, between 2015 and 2020, with a keyword search that focused on natural products, natural compounds, phytomedicine, Chinese medicine, antitumor, and mitochondria. Many natural products have been studied to have antitumor effects on different cells and can be further processed into useful drugs to treat cancer. In the process of searching for valuable new drugs, natural products such as terpenoids, flavonoids, saponins, alkaloids, coumarins, and quinones cover the broad space.

show abstract

Piperazine‐Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens

et al. 2022

Self Cite

View full text Add to dashboard Cite

Ketoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ′ efficacy and safety no longer justify its use as a first‐line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we selected KTZ as a molecular scaffold to introduce such chemical modifications. We prepared a series of piperazine‐modified KTZ derivatives and we evaluated their in vitro antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of Trypanosoma parasites. Several compounds were more effective against the pathogens than KTZ. Compound 5 was 24 times more potent against Aspergillus flavus and 8 times more potent against A. fumigatus than KTZ, with similarly low cytotoxicity to HEK cells up to 100 μM. Derivative 6 had 9‐ and 7‐fold higher activity against T. brucei gambiense and T. brucei brucei than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC50 values. Combined, our findings will foster further research of piperazine‐modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.

show abstract

Quambalarine B, a Secondary Metabolite from Quambalaria cyanescens with Potential Anticancer Properties

Cited by 9 publications

References 47 publications

Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B

Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B

Natural Products Targeting the Mitochondria in Cancers

Piperazine‐Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens

Contact Info

Product

Resources

About