TY  - JOUR
AU  - Mijatović, Sanja
AU  - Pešić, Milica
AU  - Mojić, Marija
AU  - Banković, Jasna
AU  - Miljković, Đorđe
AU  - Fagone, Paolo
AU  - Mangano, Katia
AU  - Nicoletti, Ferdinando
AU  - Mccubrey, James
AU  - Tanić, Nikola
AU  - Maksimović-Ivanić, Danijela
PY  - 2013
PY  - 2013
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/508
AB  - Background: The NO-modified form of the HIV inhibitor saquinavir (Saq-NO) inhibited the growth of a variety of cancer cell lines in vitro and in vivo more potently than the original compound in a nontoxic fashion. In addition, chemo- and immunosensitizing properties were observed. The aim of the present study was to evaluate its anticancer action against non-small cell lung carcinoma cells in their doxorubicin (DOXO) sensitive and resistant phenotype (NCI-H460 and NCI-H460/R). Methods: The viability of cells was analyzed by MTT and crystal violet assays. DR5 expression was estimated by real time RT-PCR and flow cytometry. Activity of P-glycoprotein (P-gp) pumps was evaluated by the Rho123 accumulation assay. Results: Saq-NO diminished the viability of lung cancer cells through induction of cell cycle arrest in the G0/G1 phase independently of the overexpression of the P-gp pumps. In addition, Saq-NO elevated or completely reconstituted the doxorubicin efficacy in NCI-H460 and NCI-H460/R, respectively. The chemosensitizing effect in DOXO resistant cells was a consequence of P-gp inhibition which was found to be more potent than that observed with dex-verapamil, a conventional inhibitor of P-gp. Sensitization to DOXO upon Saq-NO was accompanied by elevated DR5 expression, but the resistance to TRAIL was not abrogated. Conclusions: The NO-modified HIV inhibitor saquinavir displayed equal antiproliferative and chemosensitizing properties in DOXO sensitive and resistant non-small cell lung carcinoma cells, suggesting the importance of the evaluation of this drug as an antineoplastic agent.
AB  - Uvod: Inhibitor HIV proteaze - sakvinavir nakon modifikacije kovalentnim vezivanjem NO (Saq-NO) gubi toksična svojstva dok potentnije od originalnog jedinjenja inhibira in vitro i in vivo rast brojnih ćelijskih linija kancera. Pored direktnog antitumorskog delovanja, Saq-NO povećava osetljivost ćelija kancera na antitumorski imunski odgovor i konvencionalnu hemioterapiju. Ova studija je imala za cilj ispitivanje antitumorskog potencijala Saq-NO na ćelijskim linijama nesitnoćelijskog karcinoma pluća, senzitivnim (NCI-H460), odnosno rezistentnim (NCI-H460/R) na doksorubicin. Metode: Vijabilitet ćelija je evaluiran testovima MTT i 'kristal violet'. Ekspresija receptora DR5 je procenjivana me-odom RT-PCR u realnom vremenu i protočnom citofluorimetrijom. Aktivnost P-gp pumpi određivana je akumulacionim testom Rho123. Rezultati: Saq-NO inhibira rast ćelija kancera pluća zaustavljanjem ćelija u fazi G0/G1 ćelijskog ciklusa a zapaženi efekat nije oslabljen povećanjem ekspresije P-gp pumpi. Pored toga, Saq-NO povećava osetljivost NCI-H460 ćelija, dok u slučaju rezistentne forme, NCI-H460/R, potpuno rekonstituiše njihovu osetljivost na doksorubicin. Efekat hemosenzitizacije je posledica inhibicije P-gp pumpi, što Saq-NO čini potentnijim od deksverapamila, uobičajenog inhibitora P-gp. Opisani fenomen je praćen povećanjem ekspresije receptora DR5 na genskom i membranskom nivou, ali time rezistencija na molekul TRAIL nije ukinuta. Zaključak: Saq-NO pokazuje značajan antiproliferativan i hemosenzitizujući potencijal na ćelijama nesitnoćelijskog kancera pluća nezavisno od njihove osetljivosti odnosno rezistencije na doksorubicin, ukazujući na potrebu daljeg ispitivanja ovog jedinjenja u svojstvu potencijalnog antineoplastičnog agensa.
T2  - Journal of Medical Biochemistry
T1  - Modifikovana forma sakvinavira efikasno suprimira rast ćelija nesitnoćelijskog karcinoma pluća različite osetljivosti na doksorubicin
T1  - No-modified saquinavir is equally efficient against doxorubicin sensitive and resistant non-small cell lung carcinoma cells
IS  - 4
VL  - 32
DO  - 10.2478/jomb-2013-0050
SP  - 406
EP  - 416
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_508
ER  - 

@article{
author = "Mijatović, Sanja and Pešić, Milica and Mojić, Marija and Banković, Jasna and Miljković, Đorđe and Fagone, Paolo and Mangano, Katia and Nicoletti, Ferdinando and Mccubrey, James and Tanić, Nikola and Maksimović-Ivanić, Danijela",
year = "2013, 2013",
abstract = "Background: The NO-modified form of the HIV inhibitor saquinavir (Saq-NO) inhibited the growth of a variety of cancer cell lines in vitro and in vivo more potently than the original compound in a nontoxic fashion. In addition, chemo- and immunosensitizing properties were observed. The aim of the present study was to evaluate its anticancer action against non-small cell lung carcinoma cells in their doxorubicin (DOXO) sensitive and resistant phenotype (NCI-H460 and NCI-H460/R). Methods: The viability of cells was analyzed by MTT and crystal violet assays. DR5 expression was estimated by real time RT-PCR and flow cytometry. Activity of P-glycoprotein (P-gp) pumps was evaluated by the Rho123 accumulation assay. Results: Saq-NO diminished the viability of lung cancer cells through induction of cell cycle arrest in the G0/G1 phase independently of the overexpression of the P-gp pumps. In addition, Saq-NO elevated or completely reconstituted the doxorubicin efficacy in NCI-H460 and NCI-H460/R, respectively. The chemosensitizing effect in DOXO resistant cells was a consequence of P-gp inhibition which was found to be more potent than that observed with dex-verapamil, a conventional inhibitor of P-gp. Sensitization to DOXO upon Saq-NO was accompanied by elevated DR5 expression, but the resistance to TRAIL was not abrogated. Conclusions: The NO-modified HIV inhibitor saquinavir displayed equal antiproliferative and chemosensitizing properties in DOXO sensitive and resistant non-small cell lung carcinoma cells, suggesting the importance of the evaluation of this drug as an antineoplastic agent., Uvod: Inhibitor HIV proteaze - sakvinavir nakon modifikacije kovalentnim vezivanjem NO (Saq-NO) gubi toksična svojstva dok potentnije od originalnog jedinjenja inhibira in vitro i in vivo rast brojnih ćelijskih linija kancera. Pored direktnog antitumorskog delovanja, Saq-NO povećava osetljivost ćelija kancera na antitumorski imunski odgovor i konvencionalnu hemioterapiju. Ova studija je imala za cilj ispitivanje antitumorskog potencijala Saq-NO na ćelijskim linijama nesitnoćelijskog karcinoma pluća, senzitivnim (NCI-H460), odnosno rezistentnim (NCI-H460/R) na doksorubicin. Metode: Vijabilitet ćelija je evaluiran testovima MTT i 'kristal violet'. Ekspresija receptora DR5 je procenjivana me-odom RT-PCR u realnom vremenu i protočnom citofluorimetrijom. Aktivnost P-gp pumpi određivana je akumulacionim testom Rho123. Rezultati: Saq-NO inhibira rast ćelija kancera pluća zaustavljanjem ćelija u fazi G0/G1 ćelijskog ciklusa a zapaženi efekat nije oslabljen povećanjem ekspresije P-gp pumpi. Pored toga, Saq-NO povećava osetljivost NCI-H460 ćelija, dok u slučaju rezistentne forme, NCI-H460/R, potpuno rekonstituiše njihovu osetljivost na doksorubicin. Efekat hemosenzitizacije je posledica inhibicije P-gp pumpi, što Saq-NO čini potentnijim od deksverapamila, uobičajenog inhibitora P-gp. Opisani fenomen je praćen povećanjem ekspresije receptora DR5 na genskom i membranskom nivou, ali time rezistencija na molekul TRAIL nije ukinuta. Zaključak: Saq-NO pokazuje značajan antiproliferativan i hemosenzitizujući potencijal na ćelijama nesitnoćelijskog kancera pluća nezavisno od njihove osetljivosti odnosno rezistencije na doksorubicin, ukazujući na potrebu daljeg ispitivanja ovog jedinjenja u svojstvu potencijalnog antineoplastičnog agensa.",
journal = "Journal of Medical Biochemistry",
title = "Modifikovana forma sakvinavira efikasno suprimira rast ćelija nesitnoćelijskog karcinoma pluća različite osetljivosti na doksorubicin, No-modified saquinavir is equally efficient against doxorubicin sensitive and resistant non-small cell lung carcinoma cells",
number = "4",
volume = "32",
doi = "10.2478/jomb-2013-0050",
pages = "406-416",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_508"
}

Mijatović, S., Pešić, M., Mojić, M., Banković, J., Miljković, Đ., Fagone, P., Mangano, K., Nicoletti, F., Mccubrey, J., Tanić, N.,& Maksimović-Ivanić, D.. (2013). Modifikovana forma sakvinavira efikasno suprimira rast ćelija nesitnoćelijskog karcinoma pluća različite osetljivosti na doksorubicin. in Journal of Medical Biochemistry, 32(4), 406-416.
https://doi.org/10.2478/jomb-2013-0050
https://hdl.handle.net/21.15107/rcub_ibiss_508

Mijatović S, Pešić M, Mojić M, Banković J, Miljković Đ, Fagone P, Mangano K, Nicoletti F, Mccubrey J, Tanić N, Maksimović-Ivanić D. Modifikovana forma sakvinavira efikasno suprimira rast ćelija nesitnoćelijskog karcinoma pluća različite osetljivosti na doksorubicin. in Journal of Medical Biochemistry. 2013;32(4):406-416.
doi:10.2478/jomb-2013-0050
https://hdl.handle.net/21.15107/rcub_ibiss_508 .

Mijatović, Sanja, Pešić, Milica, Mojić, Marija, Banković, Jasna, Miljković, Đorđe, Fagone, Paolo, Mangano, Katia, Nicoletti, Ferdinando, Mccubrey, James, Tanić, Nikola, Maksimović-Ivanić, Danijela, "Modifikovana forma sakvinavira efikasno suprimira rast ćelija nesitnoćelijskog karcinoma pluća različite osetljivosti na doksorubicin" in Journal of Medical Biochemistry, 32, no. 4 (2013):406-416,
https://doi.org/10.2478/jomb-2013-0050 .,
https://hdl.handle.net/21.15107/rcub_ibiss_508 .