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  • Mijatovic, Sanja  (29)
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  • 1
    In: International Journal of Cancer, 15 April 2017, Vol.140(8), pp.1713-1726
    Description: The possible use of HIV protease inhibitors (HIV‐PI) as new therapeutic option for the treatment of cancer primarily originated from their success in treating HIV‐related Kaposi's sarcoma (KS). While these findings were initially attributed to immune reconstitution and better control of oncogenic viral infections, the number of reports on solid tumors, KS, lymphoma, fibrosarcoma, multiple myeloma and prostate cancer suggest other mechanisms for the anti‐neoplastic activity of PIs. However, a major drawback for the possible adoption of HIV‐PIs in the therapy of cancer relies on their relatively weak anticancer potency and important side effects. This has propelled several groups to generate derivatives of HIV‐PIs for anticancer use, through modifications such as attachment of different moieties, ligands and transporters, including saquinavir‐loaded folic acid conjugated nanoparticles and nitric oxide (NO) derivatives of HIV‐PIs. In this article, we discuss the current preclinical and clinical evidences for the potential use of HIV‐PIs, and of novel derivatives, such as saquinavir‐NO in the treatment of cancer.
    Keywords: Hiv Protease Inhibitors ; Saquinavir‐No ; Cancer Therapeutics
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 2
    Language: English
    In: Immunologic Research, 2012, Vol.52(1), pp.157-168
    Description: Development of resistance to TRAIL-induced toxicity is one of the strategies used from tumor cells to escape destruction from the immune system. This process may occur through aberrant expression of functional receptors, overexpression of decoy receptors on tumor cell membrane, or malfunctioning of downstream signals triggered by specific ligation of TRAIL. Numerous cytostatic, but also noncytostatic, drugs like protease inhibitors and NO-hybridized molecules have been shown to revert sensitivity of neoplastic cells to TRAIL by means of different mechanisms. This paper will review the possible routes of reconstitution of sensitivity to TRAIL-mediated immune response by specific modulation of different signals responsible for the development of resistance at both the membrane and the intracellular levels. Moreover, we will review and suggest novel strategies, aimed at resetting immune cell efficiency in cancer treatment.
    Keywords: TRAIL resistance ; Death receptors ; Saquinavir-NO
    ISSN: 0257-277X
    E-ISSN: 1559-0755
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  • 3
    Language: English
    In: Biotechnology Advances, 01 November 2018, Vol.36(6), pp.1622-1632
    Description: Differentiation of cancer cells entails the reversion of phenotype from malignant to the original. The conversion to cell type characteristic for another tissue is named transdifferentiation. Differentiation/transdifferentiation of malignant cells in high grade tumor mass could serve as a nonaggressive approach that potentially limits tumor progression and augments chemosensitivity. While this therapeutic strategy is already being used for treatment of hematological cancers, its feasibility for solid malignancies is still debated. We will presently discuss the natural compounds that show these properties, with focus on anthraquinones from , Senna, Rheum sp. and hop derived prenylflavonoids.
    Keywords: Cancer ; Solid Tumors ; Blood Tumors ; Brain Tumors ; Neurooncology ; Transdifferentiation ; Chemotherapy ; Differentiation Based Therapies ; Naturally Occurring Compounds ; Aloe Emodin ; Isoxanthohumol ; Medicine ; Engineering
    ISSN: 0734-9750
    E-ISSN: 1873-1899
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  • 4
    In: Journal of Medical Biochemistry, 10/1/2013, Vol.32(4), pp.406-416
    Description: SummaryBackground: The NO-modified form of the HIV inhibitor saquinavir (Saq-NO) inhibited the growth of a variety of can- cer cell lines in vitro and in vivo more potently than the orig- inal 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 doxoru- bicin (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 Gq/G1 phase in- dependently 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, respec- tively. 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 con- ventional 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 dis- played equal antiproliferative and chemosensitizing proper- ties in DOXO sensitive and resistant non-small cell lung car- cinoma cells, suggesting the importance of the evaluation of this drug as an antineoplastic agent.Kratak sadržajUvod: Inhibitor HIV proteaze- sakvinavir nakon modifikaci- je kovalentnim vezivanjem NO (Saq-NO) gubi toksična svoj- stva dok potentnije od originalnog jedinjenja inhibira in vitro i in vivo rast brojnih čelijskih linija kancera. Pored direktnog antitumorskog delovanja, Saq-NO povečava osetljivost čelija kancera na antitumorski imunski odgovor i konvencionalnu hemioterapiju. Ova študija je imala za cilj ispitivanje antitu- morskog potencijala Saq-NO na čelijskim linijama nesitno- čelijskog karcinoma pluča, senzitivnim (NCI-H460), odnos- no rezistentnim (NCI-H460/R) na doksorubicin.Metode: Vijabilitet čelija je evaluiran testovima MTT i »kristal violet«. Ekspresija receptora DR5 je procenjivana metodom RT-PCR u reálnom vremenu i protočnom citofluorimetrijom. Aktivnost P-gp pumpi odredivana je akumulacionim testom Rho123.Rezultati: Saq-NO inhibira rast čelija kancera pluča zausta- vljanjem čelija u fazi Gq/G^ čelijskog ciklusa a zapaženi efe- kat nije oslabljen povečanjem ekspresije P-gp pumpi. Pored toga, Saq-NO povečava osetljivost NCI-H460 čelija, dok u slučaju rezistentne forme, NCI-H460/R, potpuno rekonstituiše njihovu osetljivost na doksorubicin. Efekat hemosenziti- zacije je posledica inhibicije P-gp pumpi, što Saq-NO čini potentnijim od deksverapamila, uobičajenog inhibitora P-gp. Opisani fenomen je pračen povečanjem ekspresije receptora DR5 na genskom i membranskom nivou, ali time rezistencija na molekul TRAIL nije ukinuta.Zaključak: Saq-NO pokazuje značajan antiproliferativan i hemosenzitizujuči potencijal na čelijama nesitnočelijskog kancera pluča nezavisno od njihove osetljivosti odnosno rezistencije na doksorubicin, ukazujuči na potrebu daljeg ispitivanja ovog jedinjenja u svojstvu potencijalnog antineo- plastičnog agensa.
    Keywords: Medicine;
    ISSN: 1452-8258
    E-ISSN: 1452-8266
    Source: CrossRef
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  • 5
    Language: English
    In: Molecules, 01 September 2018, Vol.23(10), p.2463
    Description: Glioblastoma (GBM) is the most frequent and deadly form of primary malignant brain tumor among adults. A promising emerging approach for GBM treatment may be offered from HIV protease inhibitors (HIV-PIs). In fact, in addition to their primary pharmacological activity in the treatment of HIV infection, they possess important anti-neoplastic effects. According to previous studies, the addition of a nitric oxide (NO) donating group to parental compounds can reduce their toxicity and enhance the anticancer action of various compounds, including HIV-PIs. In this study we compared the effects of the HIV-PI Lopinavir (Lopi) and of its NO-derivative Lopinavir-NO (Lopi-NO) on the in vitro growth of LN-229 and U-251 human GBM cell lines. Lopi-NO reduced the viability of LN-229 and U-251 cells at significantly lower concentrations than the parental drug. In particular, Lopi-NO inhibited tumor cell proliferation and induced the differentiation of U-251 cells toward an astrocyte-like phenotype without triggering significant cell death in both cell types. The anticancer effect of Lopi-NO was persistent even upon drug removal. Furthermore, Lopi-NO induced strong autophagy that did not appear to be related to its chemotherapeutic action. Overall, our results suggest that Lopi-NO could be a potential effective anticancer drug for GBM treatment.
    Keywords: Glioblastoma ; HIV Protease Inhibitors ; Lopinavir ; Lopinavir-No ; Nitric Oxide ; Chemistry
    E-ISSN: 1420-3049
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  • 6
    Language: English
    In: Free Radical Biology and Medicine, 2010, Vol.48(8), pp.1090-1099
    Description: The new chemical entity GIT-27NO was created by the covalent linkage of a NO moiety to the anti-inflammatory isoxazoline VGX-1027. The compound has been shown to possess powerful anticancer effects both in vitro and in vivo. However, its effects on nonsolid and metastatic forms of tumors have not yet been investigated. We have studied the effects of GIT-27NO on the highly invasive mouse mammary TA3Ha cell line in vitro and in vivo. In contrast to the conventional exogenous NO donor sodium nitroprusside, GIT-27NO successfully enhanced intracellular NO concentration in TA3Ha cells. Intracellular accumulation of NO was followed by marked decrease in TA3Ha cell viability accompanied by typical apoptotic features. Interestingly, inverted membrane phosphatidylserine residues, reduced volume of nucleus, condensed chromatin, and terminal fragmentation of DNA were associated with inhibited caspase-3 activity and transcription of the genes encoding caspase-3, -8, and -9. In parallel, GIT-27NO rapidly but transiently prevented the loss of p53 through phosphorylation on Ser 20 and provided the necessary signals for the execution of downstream processes without p53 de novo synthesis. The caspase-independent apoptotic-like death process triggered by GIT-27NO could be mediated by markedly down-regulated expression of the antiapoptotic Bcl-2 molecule observed in TA3Ha cells exposed to GIT-27NO. In agreement with these in vitro data, GIT-27NO efficiently suppressed the growth of the ascites form and associated lethality of tumor induced by TA3Ha cells in mice.
    Keywords: Breast Cancer ; Ta3ha ; Apoptosis ; Caspases ; P53 ; Bcl-2 ; Git-27no ; Nitric Oxide ; Free Radicals ; Biology ; Anatomy & Physiology
    ISSN: 0891-5849
    E-ISSN: 1873-4596
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  • 7
    Language: English
    In: Cell Cycle, 15 March 2012, Vol.11(6), pp.1174-1182
    Description: We previously reported that the NO-modified form of HIV protease inhibitor Saquinavir (Saq) is a potent antitumoral agent efficient against numerous tumor cell lines in vitro and in vivo. In acute toxicity studies, doses of Saq-NO equivalent to DL100 of the parental drug were completely nontoxic....
    Keywords: Xiap ; Trail ; S6 Protein ; Saquinavir ; Saquinavir-No ; Biology
    ISSN: 1538-4101
    E-ISSN: 1551-4005
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  • 8
    Language: English
    In: Journal of cellular physiology, July 2011, Vol.226(7), pp.1803-12
    Description: We have recently shown that covalent attachment of the NO moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity. In this study we evaluated the impact of Saq-NO on the growth of A375 human melanoma cells, as a prototype of NO-dependent cancer model. The novel compound strongly affected the in vitro and in vivo progression of A375 melanoma cell growth. The mechanism of antimelanoma action comprised dual drug activity-induction of apoptotic cell death and acquisition of melanoma cell responsiveness to TRAIL. Saq-NO-triggered apoptosis was dependent on transient AKT up-regulation and reduced pERK and iNOS expression that were observed within the first 12 h of exposure to the drug. Thereafter, however, Saq-NO up-regulated both iNOS transcription and NO endogenous synthesis and sensitized A375 cells to TRAIL. Furthermore, reduced YY1 expression was observed after 24 h of Saq-NO exposure, which correlated with increased expression of DR5. The biological relevance of this complex and powerful action of Saq-NO was consistent with the marked drug-induced inhibition of the growth of A375 xenotransplants in nude mice.
    Keywords: Antineoplastic Agents -- Pharmacology ; Cell Proliferation -- Drug Effects ; Melanoma -- Drug Therapy ; Nitric Oxide Synthase Type II -- Metabolism ; Saquinavir -- Analogs & Derivatives ; Tnf-Related Apoptosis-Inducing Ligand -- Pharmacology
    ISSN: 00219541
    E-ISSN: 1097-4652
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  • 9
    Language: English
    In: Molecular pharmacology, October 2012, Vol.82(4), pp.700-10
    Description: We have examined the influence of the nitric oxide (NO)-modified anti-inflammatory drug (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) named GIT-27NO or the NO-modified antiviral drug saquinavir (Saq) named Saq-NO on two colon cancer cell lines, mouse CT26CL25 and human HCT116. The effects of the drugs on cell viability, apoptosis, proliferation, and metastatic potential were analyzed. The release of NO and oxygen and nitrogen species was also determined. The efficacy of the drugs was evaluated in vivo in BALB/c mice injected with CT26CL25 cells. Both agents suppressed the growth of colon cancer cells in vitro and reduced tumor volume in syngeneic BALB/c mice. However, their mechanisms of action were different because GIT-27NO released larger amounts of nitrite than Saq-NO in cell cultures and its antitumor action depended on the intracellular NO release inside the cells. On the contrary, Saq-NO released barely detectable amounts of NO and its antitumor action was NO-independent. In fact, cotreatment with an NO-peroxynitrite scavenger revealed that GIT-27NO but not Saq-NO acts through peroxynitrite-mediated cell destruction. At the cellular level, GIT-27NO prevalently induced proapoptotic signals followed by caspase-dependent apoptosis. In contrast, Saq-NO blocked cell proliferation, changed the adhesive, migratory, and invasive properties of the cells, and decreased metastatic potential in vivo. In conclusion, differences in NO release and oxidative stress generation between GIT-27NO and Saq-NO resulted in different mechanisms that caused cell death.
    Keywords: Acetates -- Pharmacology ; Antineoplastic Agents -- Pharmacology ; Colonic Neoplasms -- Drug Therapy ; Nitric Oxide -- Chemistry ; Oxazoles -- Pharmacology ; Saquinavir -- Pharmacology
    E-ISSN: 1521-0111
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  • 10
    Language: English
    In: Leukemia Research, October 2015, Vol.39(10), pp.1088-1095
    Description: Covalent attachment of NO to the first approved HIV protease inhibitor Saquinavir (Saq-NO) expands the therapeutic potential of the original drug. Apart from retained antiviral activity, the modified drug exerts strong antitumor effects and lower toxicity. In the present study, we have evaluated the sensitivity of different hematological malignancies to Saq-NO. Saq-NO efficiently diminished the viability of Jurkat, Raji, HL-60 and K562 cells. While Jurkat and Raji cells (established from pediatric patients) displayed abrogated proliferative potential, HL-60 and K652 cells (originated from adults) exposed to Saq-NO treatment underwent caspase dependent apoptosis. In addition, similar sensitivity to Saq-NO was observed in mononuclear blood cells obtained from pediatric patients with acute lymphoblastic leukemia (ALL) and adult patients with acute myeloid leukemia (AML). Western blot analysis indicated p70S6 kinase as a possible intracellular target of Saq-NO action. Moreover, the addition of a NO moiety to Lopinavir resulted in improved antitumor potential as compared to the parental compound, suggesting that NO-derived HIV protease inhibitors are a potential new source of anticancer drugs with unique mode of action.
    Keywords: Saquinavir ; Saquinavir-No ; Acute Lymphoid Leukemia ; Acute Myeloid Leukemia ; P70s6 Kinase ; Medicine
    ISSN: 0145-2126
    E-ISSN: 1873-5835
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