2024. gadā aizstāvētie promocijas darbi un kopsavilkumi

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Browsing 2024. gadā aizstāvētie promocijas darbi un kopsavilkumi by Author "Arsenjans, Pāvels"

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    Izoselenazolija sāļu ietekme uz vēža metabolismu. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2024) Dimitrijevs, Pāvels; Arsenjans, Pāvels
    Zema terapeitiska efektivitāte un rezistence pret esošām zālēm joprojām ir galvenie šķēršļi mūsdienu ķīmijterapijā. Tāpēc zinātnieki visā pasaulē nemitīgi meklē jaunas zāļvielas ar dažādiem darbības mehānismiem, kas, atsevišķi vai kombinācijā ar citām zālēm, palīdzēs pacientiem ar vēzi. Pēdējos gados selēnu saturošie savienojumi, raksturīgo selēna īpašību dēļ, tiek plaši pētīti kā pretvēža līdzekļi. Šī promocijas darba galvenais mērķis bija novērtēt izoselenazolija sāļu, jaunas organisko selēna savienojumu klases, ķīmijterapijas potenciālu un izpētīt to darbības mehānismu. Pirmā izoselenazolija sāļu sērija uzrādīja selektīvu citotoksicitāti pret krūts vēža šūnu līnijām. Šie savienojumi modulēja mitohondriālo elpošanu, palielināja reaktīvā skābekļa savienojumu veidošanos, ietekmēja NAD+ homeostāzi, kavēja poli(ADP-ribozes) polimerāzi 1 (PARP1) un, iespējams, mijiedarbojās ar mitohondrijiem raksturīgo fosfolipīdu – kardiolipīnu. Lai pārbaudītu pēdējo apgalvojumu, tika izstrādāts jauns kardiolipīnam specifiskais fluorescējošais marķieris un uz konkurējošās saistīšanās balstīta metode, lai kvantitatīvi raksturotu zāļu afinitāti pret kardiolipīnu. Izmantojot jaunu metodi, tika pierādīts, ka izoselenazolija sāļu afinitāte pret kardiolipīnu ir zema, un viņu savstarpēja mijiedarbība nav saistīta ar farmakoloģisko efektu. Otrā izoselenazolija sāļu sērija ar modificētu struktūru tika izstrādāta, lai uzlabotu PARP1 kavējošo aktivitāti. Šiem savienojumiem tika pierādīta augsta citotoksicitāte pret T-šūnu leikēmijas, krūts, aknu un plaušu vēža šūnām. Lai gan PARP1 kavējošā aktivitāte tika uzlabota, detalizēti darbības mehānisma pētījumi parādīja, ka izoselenazolija sāļi spēcīgi un selektīvi kavē piruvāta kināzi M2 (PKM2), enzīmu, kas ir augsti ekspresēta dažādos audzējos. Pamatojoties uz KMR, izmēru izslēgšanas hromatogrāfijas, masas fotometrijas, diferenciālās skenēšanas fluorimetrijas, izotermiskās titrēšanas kalorimetrijas un enzīma kinētikas datiem, tika konstatēts, ka izoselenazolija sāļiem piemīt konkurējošo inhibitoru raksturs, un, tajā pašā laikā tie izraisa nestabilu PKM2 homotetramēru veidošanos. Tādējādi tiek bloķēta PKM2 translokācija uz šūnas kodolu, novēršot tā nemetaboliskās funkcijas. Spēcīgu PKM2 inhibitoru atklāšana var kalpot par pamatu jauniem pretvēža zāļu kandidātiem un sniegt svarīgu ieskatu par PKM2 lomu onkoģenēzē.
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    Targeting Cancer Metabolism with Isoselenazolium Salts. Doctoral Thesis
    (Rīga Stradiņš University, 2024) Dimitrijevs, Pāvels; Arsenjans, Pāvels
    Low therapeutic efficacy and resistance to conventional drugs remain the major obstacles in modern chemotherapy. Scientists around the world are therefore constantly searching for new drugs with different modes of action that, alone or in combination with other drugs, can help cancer patients. In recent years, selenium-containing compounds have been extensively studied as anticancer agents due to the characteristic properties of selenium. The main aim of this study was to evaluate the chemotherapeutic potential of isoselenazolium salts, a novel class of organoselenium compounds, and to explore their mechanism of action. The first series of isoselenazolium salts exhibited selective cytotoxicity against breast cancer cell lines. These compounds modulated mitochondrial respiration, increased reactive oxygen species production, altered NAD+ homeostasis, inhibited poly(ADP-ribose) polymerase 1 (PARP1) and possibly interfered with cardiolipin, a signature phospholipid of mitochondria. To test the latter, a new fluorescent cardiolipin-specific probe and a competitive binding assay were developed to quantitatively describe the drugs` affinity for cardiolipin. Using a new method, it was proved that the affinity of isoselenazolium salts for cardiolipin is low, and their interaction is not related to the pharmacological effect. The second series of isoselenazolium salts with a modified structure was designed to have improved PARP1 inhibitory activity. These compounds displayed high cytotoxicity against T-cell leukaemia, breast, liver, and lung cancer cells. Although the PARP1 inhibitory activity was improved, detailed studies of the mechanism of action showed that isoselenazolium salts are potent and selective inhibitors of pyruvate kinase M2 (PKM2), an enzyme, that is highly expressed in various types of tumours. On the basis of NMR, size-exclusion chromatography, mass photometry, differential scanning fluorimetry, isothermal titration calorimetry, and enzyme kinetic data, isoselenazolium salts were found to be competitive inhibitors and at the same time induce an unstable PKM2 homotetramer formation. Thus, PKM2 translocation to the nucleus is blocked, preventing its nonmetabolic functions. The discovery of robust PKM2 inhibitors could serve as the basis for new anticancer drug candidates and provide an important insight into the fundamental role of PKM2 in oncogenesis.
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    Targeting Cancer Metabolism with Isoselenazolium Salts. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2024) Dimitrijevs, Pāvels; Arsenjans, Pāvels
    Low therapeutic efficacy and resistance to conventional drugs remain the major obstacles in modern chemotherapy. Scientists around the world are therefore constantly searching for new drugs with different modes of action that, alone or in combination with other drugs, can help cancer patients. In recent years, selenium-containing compounds have been extensively studied as anticancer agents due to the characteristic properties of selenium. The main aim of this study was to evaluate the chemotherapeutic potential of isoselenazolium salts, a novel class of organoselenium compounds, and to explore their mechanism of action. The first series of isoselenazolium salts exhibited selective cytotoxicity against breast cancer cell lines. These compounds modulated mitochondrial respiration, increased reactive oxygen species production, altered NAD+ homeostasis, inhibited poly(ADP-ribose) polymerase 1 (PARP1) and possibly interfered with cardiolipin, a signature phospholipid of mitochondria. To test the latter, a new fluorescent cardiolipin-specific probe and a competitive binding assay were developed to quantitatively describe the drugs` affinity for cardiolipin. Using a new method, it was proved that the affinity of isoselenazolium salts for cardiolipin is low, and their interaction is not related to the pharmacological effect. The second series of isoselenazolium salts with a modified structure was designed to have improved PARP1 inhibitory activity. These compounds displayed high cytotoxicity against T-cell leukaemia, breast, liver, and lung cancer cells. Although the PARP1 inhibitory activity was improved, detailed studies of the mechanism of action showed that isoselenazolium salts are potent and selective inhibitors of pyruvate kinase M2 (PKM2), an enzyme, that is highly expressed in various types of tumours. On the basis of NMR, size-exclusion chromatography, mass photometry, differential scanning fluorimetry, isothermal titration calorimetry, and enzyme kinetic data, isoselenazolium salts were found to be competitive inhibitors and at the same time induce an unstable PKM2 homotetramer formation. Thus, PKM2 translocation to the nucleus is blocked, preventing its nonmetabolic functions. The discovery of robust PKM2 inhibitors could serve as the basis for new anticancer drug candidates and provide an important insight into the fundamental role of PKM2 in oncogenesis.