Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

• MeSH
• energetický metabolismus MeSH
• ethery metabolismus   MeSH
• glycerolfosfátdehydrogenasa * genetika   metabolismus   MeSH
• lidé MeSH
• mitochondrie * enzymologie   MeSH
• myši MeSH
• nádory * enzymologie   patologie   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

P21-activated kinases (PAKs) regulate processes associated with cytoskeletal rearrangements, such as cell division, adhesion, and migration. The possible regulatory role of PAKs in cell metabolism has not been well explored, but increasing evidence suggests that a cell metabolic phenotype is related to cell interactions with the microenvironment. We analyzed the impact of PAK inhibition by small molecule inhibitors, small interfering RNA, or gene knockout on the rates of mitochondrial respiration and aerobic glycolysis. Pharmacological inhibition of PAK group I by IPA-3 induced a strong decrease in metabolic rates in human adherent cancer cell lines, leukemia/lymphoma cell lines, and primary leukemia cells. The immediate effect of FRAX597, which inhibits PAK kinase activity, was moderate, indicating that PAK nonkinase functions are essential for cell metabolism. Selective downregulation or deletion of PAK2 was associated with a shift toward oxidative phosphorylation. In contrast, PAK1 knockout resulted in increased glycolysis. However, the overall metabolic capacity was not substantially reduced by PAK1 or PAK2 deletion, possibly due to partial redundancy in PAK1/PAK2 regulatory roles or to activation of other compensatory mechanisms.

• MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• lidé MeSH
• mitochondrie enzymologie   genetika   MeSH
• nádorové mikroprostředí * MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• nádory enzymologie   genetika   MeSH
• p21 aktivované kinasy genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In this contribution, four new compounds synthesized from 4-hydroxycoumarin and tyramine/octopamine/norepinephrine/3-methoxytyramine are characterized spectroscopically (IR and NMR), chromatographically (UHPLC-DAD), and structurally at the B3LYP/6-311++G*(d,p) level of theory. The crystal structure of the 4-hydroxycoumarin-octopamine derivative was solved and used as a starting geometry for structural optimization. Along with the previously obtained 4-hydroxycoumarin-dopamine derivative, the intramolecular interactions governing the stability of these compounds were quantified by NBO and QTAIM analyses. Condensed Fukui functions and the HOMO-LUMO gap were calculated and correlated with the number and position of OH groups in the structures. In vitro cytotoxicity experiments were performed to elucidate the possible antitumor activity of the tested substances. For this purpose, four cell lines were selected, namely human colon cancer (HCT-116), human adenocarcinoma (HeLa), human breast cancer (MDA-MB-231), and healthy human lung fibroblast (MRC-5) lines. A significant selectivity towards colorectal carcinoma cells was observed. Molecular docking and molecular dynamics studies with carbonic anhydrase, a prognostic factor in several cancers, complemented the experimental results. The calculated MD binding energies coincided well with the experimental activity, and indicated 4-hydroxycoumarin-dopamine and 4-hydroxycoumarin-3-methoxytyramine as the most active compounds. The ecotoxicology assessment proved that the obtained compounds have a low impact on the daphnia, fish, and green algae population.

• MeSH
• 4-hydroxykumariny chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• difrakce rentgenového záření MeSH
• HCT116 buňky MeSH
• HeLa buňky MeSH
• karboanhydrasy chemie   metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   enzymologie   MeSH
• neurotransmiterové látky chemie   MeSH
• oktopamin chemie   MeSH
• proliferace buněk účinky léků   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Metformin (MTF) is a widely used drug for the treatment of diabetes mellitus type 2 (DM2) and frequently used as an adjuvant therapy for polycystic ovarian syndrome, metabolic syndrome, and in some cases also tuberculosis. Its protective effect on the cardiovascular system has also been described. Recently, MTF was subjected to various analyzes and studies that showed its beneficial effects in cancer treatment such as reducing cancer cell proliferation, reducing tumor growth, inducing apoptosis, reducing cancer risk in diabetic patients, or reducing likelihood of relapse. One of the MTF's mechanisms of action is the activation of adenosine-monophosphate-activated protein kinase (AMPK). Several studies have shown that AMPK/mammalian target of rapamycin (mTOR) pathway has anticancer effect in vivo and in vitro. The aim of this review is to present the anticancer activity of MTF highlighting the importance of the AMPK/mTOR pathway in the cancer process.

• MeSH
• antitumorózní látky škodlivé účinky   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• hypoglykemika terapeutické užití   MeSH
• lidé MeSH
• metformin škodlivé účinky   terapeutické užití   MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• signální transdukce MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.

• MeSH
• checkpoint kinasa 2 chemie   genetika   metabolismus   MeSH
• genetická predispozice k nemoci * MeSH
• lidé MeSH
• mutační rychlost MeSH
• nádory enzymologie   genetika   MeSH
• substrátová specifita MeSH
• zárodečné mutace genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Medicinal plants have been studied for potential endophytic interactions and numerous studies have provided evidence that seeds harbor diverse microbial communities, not only on their surfaces but also within the embryo. Adenosine deaminase (ADA) is known as a potential therapeutic target for the treatment of lymphoproliferative disorders and cancer. Therefore, in this study, 20 types of medicinal plant seeds were used to screen endophytic fungi with tissue homogenate and streak. In addition, 128 morphologically distinct endophyte strains were isolated and their ADA inhibitory activity determined by a spectrophotometric assay. The strain with the highest inhibitory activity was identified as Cochliobolus sp. Seven compounds were isolated from the strain using a chromatography method. Compound 3 showed the highest ADA inhibitory activity and was identified as 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one, based on the results of 1H and 13C NMR spectroscopy. The results of molecular docking suggested that compound 3 binds to the active site and the nonspecific binding site of the ADA. Furthermore, we found that compound 3 is a mixed ADA inhibitor. These results indicate that endophytic strains are a promising source of ADA inhibitors and that compound 3 may be a superior source for use in the preparation of biologically active ADA inhibitor compounds used to treat cancer.

• MeSH
• adenosindeaminasa chemie   metabolismus   MeSH
• Ascomycota chemie   klasifikace   genetika   izolace a purifikace   MeSH
• endofyty chemie   klasifikace   genetika   izolace a purifikace   MeSH
• inhibitory adenosindeaminasy chemie   farmakologie   MeSH
• léčivé rostliny mikrobiologie   MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• nádory farmakoterapie   enzymologie   MeSH
• semena rostlinná mikrobiologie   MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance.

• MeSH
• antitumorózní látky farmakologie   MeSH
• chemorezistence * účinky léků   MeSH
• exocytóza MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• lyzozomy účinky léků   enzymologie   MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   enzymologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• vakuolární protonové ATPasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Chemoresistance, radioresistance, and the challenge of achieving complete resection are major driving forces in the search for more robust and targeted anticancer therapies. Targeting the DNA damage response has recently attracted research interest, as these processes are enhanced in tumour cells. The major replication stress responder is ATM and Rad3-related (ATR) kinase, which is attracting attention worldwide with four drug candidates currently in phase I/II clinical trials. This review addresses a potent and selective small-molecule ATR inhibitor, which is known as VX-970 (also known as berzosertib or M6620), and summarizes the existing preclinical data to provide deep insight regarding its real potential. We also outline the transition from preclinical to clinical studies, as well as its relationships with other clinical candidates (AZD6738, VX-803 [M4344], and BAY1895344). The results suggest that VX-970 is indeed a promising anticancer drug that can be used both as monotherapy and in combination with either chemotherapy or radiotherapy strategies. Based on patient anamnesis and biomarker identification, VX-970 could become a valuable tool for oncologists in the fight against cancer.

• MeSH
• antitumorózní látky škodlivé účinky   terapeutické užití   MeSH
• ATM protein antagonisté a inhibitory   metabolismus   MeSH
• cílená molekulární terapie MeSH
• inhibitory proteinkinas škodlivé účinky   terapeutické užití   MeSH
• isoxazoly škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• objevování léků * MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• pyraziny škodlivé účinky   terapeutické užití   MeSH
• signální transdukce MeSH
• sulfony terapeutické užití   MeSH
• synergismus léků MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The sarco/endoplasmic reticulum calcium ATPase (SERCA), which plays a key role in the maintenance of Ca2+ ion homeostasis, is an extensively studied enzyme, the inhibition of which has a considerable impact on cell life and death decision. To date, several SERCA inhibitors have been thoroughly studied and the most notable one, a derivative of the sesquiterpene lactone thapsigargin, is gradually approaching a clinical application. Meanwhile, new compounds with SERCA-inhibiting properties of natural, synthetic, or semisynthetic origin are being discovered and/or developed; some of these might also be suitable for the development of new drugs with improved performance. This review brings an up-to-date comprehensive overview of recently discovered compounds with the potential of SERCA inhibition, discusses their mechanism of action, and highlights their potential clinical applications, such as cancer treatment.

• MeSH
• antitumorózní látky chemie   farmakologie   terapeutické užití   MeSH
• genové regulační sítě účinky léků   genetika   MeSH
• inhibitory enzymů chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   MeSH
• sarkoplazmatická Ca2+-ATPáza antagonisté a inhibitory   chemie   genetika   MeSH
• sekundární struktura proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin-converting enzyme (ACE) comprises the classical RAS. The non-classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1-7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non-classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.

• MeSH
• aktivace enzymů MeSH
• aktivátory enzymů škodlivé účinky   terapeutické užití   MeSH
• angiotensin konvertující enzym 2 metabolismus   MeSH
• diminazen škodlivé účinky   analogy a deriváty   terapeutické užití   MeSH
• kardiovaskulární nemoci farmakoterapie   enzymologie   patofyziologie   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   patofyziologie   MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH