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Uloga purinskog nukleozidnog analoga-sulfinozina u inhibiciji rasta malignih ćelija neosetljivih na dejstvo hemioterapeutika

The role of purine nucleoside analog - sulfinosine in growth inhibition of cancer cells resistant to classic chemotherapeutics

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2013
Disertacija.pdf (2.515Mb)
Author
Dačević, Mirjana P.
Mentor
Isaković, Aleksandra
Committee members
Pešić, Milica
Marković, Ivanka
Rakić, Miodrag
Ruždijić, Sabera
Metadata
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Abstract
Efikasno izlečenje tumora je veoma teško postići posebno kada se razvije višestruka rezistencija (MDR) na konvencionalnu antineoplastičnu terapiju. Visoka aktivnost Pglikoproteina (P‐gp) je ključni mehanizam razvoja MDR kod različitih tipova karcinoma. Upravo je pronalaženje antitumorskog agensa koji bi istovremeno ubijao ćelije tumora i inhibirao MDR veoma važan korak u razvoju novih terapijskih strategija za lečenje malignih oboljenja. U našem radu smo se bavili istraživanjem efekata koje sulfinozin (SF) ispoljava na dve ćelijske linije sa uspostavljenom MDR fenotipom kod kojih je P‐gp pumpa prekomerno eksprimirana (nesitnoćelijski karcinom pluća tj. NCI‐H460/R i glioblastom tj. U87‐TxR). SF je uzrokovao sličan citotoksičan efekat kod senzitivnih (NCI‐H460 i U87) i rezistentnih (NCI‐H460/R i U87‐TxR) ćelijskih linja, dok kod normalnih ćelija (HaCaT) citotoksičnost nije uočena ni pri tretmanu sa visokim dozama (100 μM). SF kod rezistentnih ćelija dovodi do indukcije apoptoze, što je p...otvrđeno i aktivacijom efektorske kaspaze 3. Apotoza zavisna od kaspaza je praćena pojavom autofagije. Nakon dejstva SF‐a dolazi do povećanja sadržaja kiseoničnih reaktivnih vrsta i smanjenja koncentracije glutationa (GSH). SF svojim delovanjem dovodi i do smanjenja ekspresije ključnog enzima glutationskog sistema γGCS i ekspresije gst‐π iRNK. Posledično, SF dovodi do značajnog smanjenja ekspresije iRNK gena koji su odgovorni za tumorsku progresiju: hif‐1α, mdr1 i vegf i u hipoksičnim uslovima. SF takođe dovodi do inhibicije ekspresije i aktvinosti P‐gp‐a. Pokazano je da SF kod rezistentnih ćelija dovodi do povećanja akumulacije standardnog hemioterapeutika doksorubicina (DOX). Svoj najbolji efekat SF ispoljava nakon 72 h i ovaj efekat je sličan efektu koji postižu tarikvidar i Dex‐verapamil. Može se zaključiti da SF dovodi do senzitizacije rezistentnih ćelijskih linija na DOX u naizmeničnom tretmanu. Uz to, SF dovodi do smanjenja ekspresije iRNK vaskularnog endotelijalnog faktora rasta (VEGF) i utiče na modulaciju njegove sekrecije. Na osnovu svega navedenog zaključujemo da se SF može klasifikovati kao multi‐potentni antikancerski agent posebno za primenu kod rezistentnih maligniteta.

Achieving an effective treatment of cancer is difficult, particularly when resistance to conventional chemotherapy is developed. P‐glycoprotein (P‐gp) activity governs multidrug resistance (MDR) development in different cancer cell types. Identification of anticancer agents with the potential to kill cancer cells and at the same time inhibit MDR is important to intensify the search for novel therapeutic approaches. We examined the effects of sulfinosine (SF), a quite unexplored purine nucleoside analog, in MDR (P‐gp over‐expressing) non‐small cell lung carcinoma (NSCLC) and glioblastoma cell lines (NCIH460/ R and U87‐TxR, respectively). SF showed the same efficacy against MDR cancer cell lines and their sensitive counterparts. However, it was non‐toxic for normal human keratinocytes (HaCaT). SF induced caspase‐dependent apoptotic cell death and autophagy in MDR cancer cells. After SF application, reactive oxygen species (ROS) were generated and glutathione (GSH) concentration was decre...ased. The expression of key enzyme for GSH synthesis, gamma Glutamyl‐cysteine‐synthetase (γGCS) was decreased as well as the expression of gst‐π mRNA. Consequently, SF significantly decreased the expression of hif‐ 1α, mdr1 and vegf mRNAs even in hypoxic conditions. SF caused the inhibition of P‐gp (coded by mdr1) expression and activity. The accumulation of standard chemotherapeutic agent – doxorubicin (DOX) was induced by SF in concentration‐ and time‐dependent manner. The best effect of SF was obtained after 72 h when it attained the effect of known P‐gp inhibitors (Dex‐verapamil and tariquidar). Accordingly, SF sensitized the resistant cancer cells to DOX in subsequent treatment. Furthermore, SF decreased the experssion of vascular endothelial growth factor (VEGF) on mRNA and protein level and modulated its secretion. In conclusion, the effects on P‐gp (implicated in pharmacokinetics and MDR), GSH (implicated in detoxification) and VEGF (implicated in tumor‐angiogenesis and progression) qualify SF as multi‐potent anti‐cancer agent, which use must be considered, in particular for resistant malignancies.

Faculty:
University of Belgrade, School of Medicine
Date:
14-10-2013
Projects:
  • Modulation of intracellular energy balance-controlling signalling pathways in therapy of cancer and neuro-immuno-endocrine disorders (RS-41025)
  • Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-41031)
Keywords:
sulfinozin (SF) / sulfinosine / višestruka rezistencija na lekove (MDR) / NSCLC ćelije (NCIH460/ R) / ćelije glioblastoma (U87‐TxR) / P‐glikoprotein / multidrug resistance / NSCLC / glioblastoma cells / P‐glycoprotein
[ Google Scholar ]
URI
http://nardus.mpn.gov.rs/handle/123456789/2427
http://eteze.bg.ac.rs/application/showtheses?thesesId=1136
https://fedorabg.bg.ac.rs/fedora/get/o:7906/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=45163535

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