Smjerovi istraživanja:

1.         Signalni putevi potaknuti integrinima u odgovoru tumorskih stanica na protutumorske lijekove i metastaziranju.

2.         Mehanizmi otpornosti tumorskih stanica na protutumorske lijekove, posebice uključenost miRNA i integrina u te procese.

3.         Novosintetizirani spojevi kao potencijalni protutumorski lijekovi.

4.         Adenovirusni vektori za prijenos gena i vakcinaciju.

Grupe:

Grupa Ambriović Ristov

Grupa Ambriović-Ristov istražuje signalne puteve potaknute integrinima u stanicama tumora čovjeka i mogućnost modulacije ekspresije integrina u cilju povećanja osjetljivosti stanica tumora na protutumorske lijekove. Osim toga, istražujemo kako ekspresija različitih integrina utječe na migraciju i invaziju stanica tumora. Predmet naših istraživanja su i fokalne adhezije, definirane kao mjesta vezanja stanice s izvanstaničnim matriksom, i to njihov sastav, stvaranje i evolucija tijekom vezanja na podlogu i migracije.

Grupa Brozović

Uspješnost kemoterapije u liječenju tumora ograničena je razvojem otpornosti tumora na lijekove i nuspojavama. Grupa Brozović se bavi proučavanjem molekularnih mehanizama uključenih u otpornost stanica tumora na lijekove. Trenutna istraživanja su usmjerena na proučavanje odnosa epitelno-mezenhimalne tranzicije, procesa uključenog u metastaziranje tumora, i razvoja otpornosti stanica tumora na lijekove. Nadalje, u svrhu poboljšanja postojeće kemoterapije, grupa se bavi proučavanjem bioloških karakteristika novosintetiziranih kompleksa organskih molekula s metalima.

Grupa Majhen

Adenovirusni vektori imaju potencijalno translacijsku i komercijalnu vrijednost, a trenutno se istražuju kao vektori za prijenos gena i vakcinaciju. U grupi Majhen bavimo se istraživanjem temeljne biologije adenovirusnih vektora i to adenovirusa tipa 5 i 26. Glavni ciljevi našeg istraživanja su pronalazak poveznica između vezanja adenovirusnog vektora na receptor na površini stanice i unutarstaničnog putovanja vektora te posljedično poticanja imunosnog odgovora. Dodatno nas zanima i način preusmjeravanja adenovirusnih vektora prema ciljnoj molekuli kao i njihovo unutarstanično putovanje.

Publikacije

2021

• De Las Rivas J, Brozovic A, Izraely S, Casas-Pais A,  Witz IP, Figueroa A. Cancer drug resistance induced by EMT: novel therapeutic strategies. Archives of Toxicology, 95, 2279-2297, 2021.
• Schijns V, Majhen D, van der Ley P, Thakur A, Summerfield A, Berisio R, Nativi C, Fernández-Tejada A, Alvarez-Dominguez C, Gizurarson S, Zamyatina A, Molinaro A, Rosano C, Jakopin Ž, Gursel I, McClean S. Rational Vaccine Design in Times of Emerging Diseases: The Critical Choices of Immunological Correlates of Protection, Vaccine Antigen and Immunomodulation. Pharmaceutics. 2021 Apr 6;13(4):501. doi: 10.3390/pharmaceutics13040501.
• Tadijan A, Samaržija I, Humphries JD, Humphries MJ, Ambriović-Ristov A. KANK family proteins in cancer. Int J Biochem Cell Biol. 2021 Feb;131:105903. doi: 10.1016/j.biocel.2020.105903. Epub 2020 Dec 10.

2020

• Šmidlehner T, Košćak M, Božinović K, Majhen D, Schmuck C, Piantanida I. Fluorimetric and CD recognition between Various ds-DNA/RNA Depends on a Cyanine Connectivity in Cyanine-guanidiniocarbonyl-pyrrole Conjugate, Molecules 2020, 25(19), 4470. doi: 10.3390/molecules25194470
• Božinović K*, Nestić D*, Centa UG, Ambriović-Ristov A, Dekanić A, de Bisschop L, Remškar M, Majhen D. In-vitro toxicity of molybdenum trioxide nanoparticles on human keratinocytes. Toxicology. 2020 Sep 4:152564. doi: 10.1016/j.tox.2020.152564. *equal contribution
• Samaržija I, Dekanić A, Humphries JD, Paradžik M, Stojanović N, Humphries MJ, Ambriović-Ristov A. Integrin Crosstalk Contributes to the Complexity of Signalling and Unpredictable Cancer Cell Fates. Cancers (Basel). 2020 Jul 15;12(7):1910. doi:10.3390/cancers 12071910.
• Erin N, Grahovac J, Brozovic A, Efferth T. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resistance Updates. 2020, Invited review, in press
• Torić J, Brozovic A^#, Baus Lončar M, Jakobušić Brala C, Karković Marković A, Benčić Đ, Barbarić M^#. Biological Activity of Phenolic Compounds in Extra Virgin Olive Oils through Their Phenolic Profile and Their Combination with Anticancer Drugs Observed in Human Cervical Carcinoma and Colon Adenocarcinoma Cells. Antioxidants (Basel). 9(5):453, 2020. ^#corresponding authors
• Paradžik M, Humphries JD, Stojanović N, Nestić D, Majhen D, Dekanić A, Samaržija I, Sedda D, Weber I, Humphries MJ, Ambriović-Ristov A. KANK2 Links αVβ5 Focal Adhesions to Microtubules and Regulates Sensitivity to Microtubule Poisons and Cell Migration. Frontiers in Cell and Developmental Biology. 8:125, 2020.
• Hulin-Curtis SL, Davies JA, Nestić D, Bates EA, Baker AT, Cunliffe TG, Majhen D, Chester JD, Parker AL. Identification of folate receptor α (FRα) binding oligopeptides and their evaluation for targeted virotherapy applications. Cancer Gene Ther. 2020 Jan 6. doi: 10.1038/s41417-019-0156-0.

2018-2019

• Kralj J*, Bolje A*, Stupin Polančec D, Gržan T, Tupek A, Steiner I, Stojanović N, Hohloch S, Urankar D, Osmak M, Sarkar B^#, Brozovic A^#, Košmrlj J^#. Half-Sandwich Ir(III) and Os(II) complexes of pyridyl-mesoionic carbenes as potential anticancer drugs. Organometallics. 38:4082-4092, 2019. *equal contribution, ^#corresponding authors, urednici časopisa Organometallics izabrali su naš prijedlog za Supplementary Cover Art koji možete vidjeti na http://pubs.acs.org/toc/orgnd7/38/21. Dodatni podaci o uspješnosti rada su navedeni na IRB stranici: https://www.irb.hr/Novosti/Rad-molekularnih-biologa-objavljen-u-uglednom-casopisu-Organometallics
• Assaraf YG, Brozovic A, Gonçalves AC, Jurkovicova D, Line A, Machuqueiro M, Saponara S, Sarmento AB, Xavier CPR, Vasconcelos MH. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resistance Updates. 2019;46:100645. doi:10.1016/j.drup.2019.100645, Invited review; sadržaj rada je istaknut na stranici Portuguese Association of Cancer Research https://www.aspic.pt/en/multi-factorial-nature-clinical-multidrug-resistance-cancer#.XhhsFvzgo2w.
• Tomicic MT, Steigerwald C, Rasenberger B, Brozovic A, Christmann M. Functional mismatch repair and inactive p53 drive sensitization of colorectal cancer cells to irinotecan via the IAP antagonist BV6. Archives of Toxicology. 93:2265-2277, 2019.
• Matić J, Šupljika F, Tandarić T, Dukši M, Piotrowski P, Vianello R, Brozovic A, Piantanida I, Schmuck C, Stojković MR. DNA/RNA recognition controlled by the glycine linker and the guanidine moiety of phenanthridine peptides. International Journal of Biological Macromolecules. 134:422-434, 2019.
• Pernar M*, Kokan Z*, Kralj J, Glasovac Z, Tumir L-M, Piantanida I, Eljuga D, Turel I, Brozovic A^#, Kirin SI^#. Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis, characterization and biological properties. Bioorganic Chemistry. 87:432-446, 2019. *equal contribution, ^#corresponding authors
• Nestić D, Uil TG, Ma J, Roy S, Vellinga J, Baker AH, Custers J, Majhen D. αvβ3 Integrin is Required for Efficient Infection of Epithelial Cells with Human Adenovirus Type 26. Journal of Virology. 93(1)e01474-18, 2018.
• Stojanović N*, Dekanić A*, Paradžik M, Majhen D, Ferenčak K, Ruščic J, Bardak I, Supina C, Tomičić MT, Christmann M, Osmak M, Ambriović-Ristov A. Differential effects of integrin αv knockdown and cilengitide on sensitisation of triple- negative breast cancer and melanoma cells to microtubule poisons. Molecular Pharmacology. 94(6)1334-1351, 2018. *equal contribution
• Grienke U, Radić Brkanac S, Vujčić V, Urban E, Ivanković S, Stojković R, Rollinger JM, Kralj J, Brozovic A*, Radić Stojković M*. Biological activity of flavonoids and rare sesquiterpene lactones isolated from Centaurea ragusina L. Frontiers in Pharmacology. 9:972, 2018. *corresponding authors
• Brozovic A. Opinion letter regarding the article Arch Toxicol https://doi.org/10.1007/s00204-018-2240-x. Archives of Toxicology. 92:3241, 2018.
• Pinterić M, Podgorski II, Sobočanec S, Popović Hadžija M, Paradžik M, Dekanić A, Marinović M, Halasz M, Belužić R, Davidović G, Ambriović Ristov A, Balog T. De novo expression of transfected sirtuin 3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment. Free Radical Research. 52:627-684, 2018.

2016-2017

• Bressy C, Majhen D, Raddi N, Jdey W, Cornilleau G, Zig L, Guirouilh-Barbat J, Lopez BS, Bawa O, Opolon P, Grellier E, Karim B. Combined therapy of colon carcinomas with an oncolytic adenovirus and valproic acid. Oncotarget. 2017; 8:97344-97360.
• Kokan Z, Perić B, Kovačević G, Brozovic A, Metzler-Nolte N, Kirin SI. Cis- vs. trans- square-planar palladium(II) and platinum(II) complexes with triphenylphosphine amino acid bioconjugates. European Journal of Inorganic Chemistry. 33:3928-3937, 2017.
• Hayek SS, Koh KH, Grams ME, Wei C, Ko Y-A, Li J, Samelko B, Lee H, Dande RR, Lee HW, Hahm E, Peev V, Tracy M, Tardi NJ, Gupta V, Altintas MM, Garborcauskas G, Stojanović N, Winkler CA, Lipkowitz MS, Tin A, Inker LA, Levey AS, Zeier M, Freedman BI, Kopp JB, Skorecki K, Coresh J, Quyyumi AA, Sever S, Reiser J. A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease. Nature Medicine. 23:945-953, 2017.
• Teofilović NK, Bihi M, Stojković MR, Tumir LM, Ester K, Kralj M, Majhen D, Oršolić N, Lepur A, Vrbanec D, Markotić A, Dembić Z, Weber AN, Piantanida I, Vugrek O, Diken M, Knežević J. 1-ethyl-3-(6-methylphenanthridine-8-il) urea modulates TLR3/9 activation and induces selective pro-inflammatory cytokine expression in vitro. Bioorg Med Chem Lett. 2017 Feb 20. pii: S0960-894X(17)30181-6. doi: 10.1016/j.bmcl.2017.02.048.
• Brozovic A. The relationship between platinum drug resistance and epithelial-mesenchymal transition. Archives of Toxicology, 91:605–619, 2017. Invited review, Godišnja nagrada Instituta Ruđer Bošković za 2017 god. u kategoriji za najbolji znanstveni rad zaposlenika koji je u trenutku objave rada imao doktorat znanost
• Christmann M., Diesler K., Majhen D., Steigerwald C., Berte N., Freund H., Stojanović N., Kaina B., Osmak M., Ambriović-Ristov A.^#, Tomicic MT^#. Integrin αVβ3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair. Oncotarget. 8(17):27754-27771, 2017. ^#corresponding authors
• Vajs J., Proud C., Brozovic A., Gazvoda M., Lloyd A., Roper D.I., Osmak M., Košmrlj J., Dowson C.G. Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis. European Journal of Medicinal Chemistry. 127:223-234, 2016.
• Ruščić J*, Ambriović-Ristov A*, Majhen D, Kolundžija S, Barut M, Benihoud K, Krajačić M. Manipulating adenoviral vector ion-exchange chromatography: Hexon versus fiber. Journal of Separation Science. 39(22):4299-4304, 2016. *equal contribution
• Stojanović N., Brozovic A., Majhen D., Bosnar M.H., Fritz G., Osmak M., Ambriović-Ristov A. Integrin αvβ3 expression in tongue squamous carcinoma cells Cal27 confers anticancer drug resistance through loss of pSrc(Y418). Biochimica et Biophysica Acta. 1863(8):1969-78, 2016. N. Stojanović je za ovaj rad dobila sljedeće nagrade: Nagrada "Željko Trgovčević" za 2016. god.; Godišnja nagrada Društva sveučilišnih nastavnika i drugih znanstvenika u Zagrebu mladim znanstvenicima i umjetnicima u 2016. god.; Godišnja nagrada Zavoda za molekularnu biologiju Instituta Ruđer Bošković za 2016. god. u kategoriji za najbolji znanstveni rad zaposlenika koji je u trenutku objave rada imao doktorat znanosti
• Sobočanec, S., Filić, V., Matovina, M., Majhen, D., Šafranko, ŽM., Hadžija, MP., Krsnik, Ž., Kurilj, AG., Šarić, A., Abramić, M., Balog, T. Prominent role of exopeptidase DPP III in estrogen-mediated protection against hyperoxia in vivo. Redox Biology. 8: 149-159, 2016. 
• Steiner I.*, Stojanović N.*, Bolje A., Brozovic A., Polančec D., Ambriović-Ristov A., Radić Stojković M., Piantanida I, Eljuga D., Košmrlj J., Osmak M. Discovery of ‘click’ 1,2,3-triazolium salts as potential anticancer drugs. Radiology and Oncology. 19;50(3):280-288, 2016. *equal contribution

2014-2015

• Brozovic A., Duran G.E., Wang Y.C., Francisco B.E., Sikic B.I. The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells. Molecular Oncology. 9(8):1678-93., 2015.
• Vajs J.*, Steiner I.*, Brozovic A.*, Pevec A., Ambriović-Ristov A., Matković M., Piantanida I., Urankar D., Osmak M., Košmrlj J. The 1,3-diaryltriazenido(p-cymene)ruthenium(II) complexes with a high in vitro anticancer activity. J Inorg Biochem. 153:42-8. 2015. *equal contribution
• Krüger K., Thomale J., Stojanovic N., Osmak M., Henninger C., Bormann S., Fritz G. Platinum-induced kidney damage: Unraveling the DNA damage response (DDR) of renal tubular epithelial and glomerular endothelial cells following platinum injury. Biochimica et Biophysica Acta. 1853: 685-698, 2015.
• Murati T., Šimić B., Brozovic A., Kniewald J., Miletić Gospić A., Bilandžić N., Kmetič I. PCB 77 action in ovary cells--toxic effects, apoptosis induction and cell cycle analysis. Toxicology Mechanisms and Methods. 25(4): 302-11., 2015.
• Majhen D., Calderon H., Chandra N., Fajardo C.A., Rajan A., Alemany R., Custers J. Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field.Human Gene Therapy. 25, 301-317, 2014.
• Majhen D., Stojanović N., Vukić D., Pichon C., Leduc C., Osmak M., Ambriović-Ristov A. Increased Adenovirus Type 5 Mediated Transgene Expression Due to RhoB Down-regulation, PLoS One. 9(1): e86698, 2014.
• Moisan F., Francisco E.B., Brozovic A., Duran G.E., Wang Y.C., Chaturvedi S., Seetharamb S., Snyder L.A., Doshi P., Sikic B.I. Enhancement of Paclitaxel and Carboplatin Therapies by CCL2 Blockade in Ovarian Cancers. Molecular Oncology. 8: 1231-1239, 2014.
• Rak S., De Zan T., Štefulj J., Kosović M., Gamulin O., Osmak M. FTIR spectroscopy reveals lipid droplets in drug resistant laryngeal carcinoma cells through detection of increased ester vibrational bands intensity. Analyst. 139, 13: 3407-3415, 2014.
• Sommer M., Kureljak P., Urankar D., Schweinfurth D., Stojanović N., Bubrin M., Gazvoda M., Osmak M., Sarkar B., Košmrlj J. Combining [Arene–Ru] with Azocarboxamide to Generate a Complex with Cytotoxic Properties. Chemistry: A European Journal, Communication. 20: 17296-17299, 2014.
• Vellinga J., Smith J.P., Lipiec A., Majhen D., Lemckert A., van Ooij M., Ives P., Yallop C., Custers J., Havenga M. Challenges in manufacturing adenoviral vectors for global vaccine product deployment. Human Gene Therapy. 25: 318-327, 2014.

2012-2013

• Brozovic A., Vuković L., Polančac D.S., Arany I., Köberle B., Fritz G., Fiket Z., Majhen D., Ambriović-Ristov A., Osmak M. Endoplasmic reticulum stress is involved in the response of human laryngeal carcinoma cells to carboplatin but is absent in carboplatin-resistant cells. PLoS One. 8(9): e76397, 2013.
• Rak S., Čimbora-Zovko T., Gajski G., Dubravčić K., Domijan A., Delaš I., Garaj-Vrhovac V., Batinić D.,  Sorić J., Osmak M. Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation. Toxicology In Vitro. 27, 2; 523-532, 2013.
• Watanabe S., De Zan T., Ishizaki T., Yasuda S., Kamijo H., Yamada D., Aoki T., Kiyonari H., Kaneko H., Shimizu R., Yamamoto M., Goshima G., Narumiya S. Loss of a Rho-regulated actin nucleator, mDia2, impairs cytokinesis during mouse fetal erythropoiesis. Cell Reports. 20135:926-932, 2013. 
• Watanabe S., De Zan T., Ishizaki T., Narumiya S. Citron kinase mediates transition from constriction to abscission through its coiled-coil domain. Journal of Cell Science. 126:1773-84, 2013.
• Gabrilovac J., Čupić B., Zapletal E., Brozović A. IFN-γ up-regulates kappa opioid receptors (KOR) on murine macrophage cell line J774. Journal of Neuroimmunology. 245, 1/2; 56-65, 2012.
• Majhen D., Richardson J., Vukelić B., Dodig I., Cindrić M., Benihoud K., Ambriović-Ristov A. The disulfide bond of an RGD4C motif inserted within the HI loop of the adenovirus type 5 fiber protein is critical for retargeting to αv-integrins. Journal of Gene Medicine. 14(12): 788-797, 2012.
• Osmak M. Statins and cancer: Current and future prospects. Cancer Letters. 324, 1; 1-12, 2012.

2010-2011

• Čimbora-Zovko T., Brozović A., Piantanida I., Fritz G., Virag A., Alič B., Majce V., Kočevar M., Polanc S., Osmak M. Synthesis and biological evaluation of 4-nitro-substituted 1, 3-diaryltriazenes as a novel class of potent antitumor agents. European Journal of Medicinal Chemistry. 46: 2971-2983, 2011.
• Gabrilovac J., Čupić B.,Živković E., Horvat L., Majhen D. Expression, regulation and functional activities of aminopeptidase N (EC 3.4.11.2 ; APN ; CD13) on murine macrophage J774 cell line. Immunobiology. 216, 1/2; 132-144, 2011.
• Helbig L., Damrot J., Hülsenbeck J., Köberle B., Brozović A., Osmak M., Fiket Ž., Kaina B., Fritz G. Late activation of stress-activated protein kinases/C-JUN-N- terminal kinases triggered by cisplatin-induced DNA damage repair defective cells. The Journal of Biological Chemistry. 286, 15; 12991-13001, 2011.
• Majhen D., Stojanović N., Špeljko T., Brozović A., De Zan T., Osmak M., Ambriović-Ristov A. Increased expression of the coxsackie and adenovirus receptor downregulates alpha v beta 3 and alpha v beta 5 integrin expression, reduces cell adehesion and migration. Life Sciences. 89: 241-249, 2011.
• Brozovic A., Ambriović-Ristov A., Osmak M. The relationship between cisplatin-induced reactive oxygen species, glutathione and BCL-2, and resistance to cisplatin. Critical Reviews in Toxicology. 40(4): 347-359, 2010.
• Majhen D*, Brozovic A*, Buger T, Gabrilovac J, Osmak M, Ambriović-Ristov A. Vincristine-resistant human laryngeal carcinoma cells demonstrate increased Rous sarcoma virus promoter activity. Life Sciences. 87(15-16):468-474, 2010.  *equal contribution
• Burja B., Čimbora-Zovko T., Tomić S., Jelušić T., Kočevar M., Polanc S., Osmak M. Pyrazolone-fused combretastatins and their precursors: synthesis, cytotoxicity, antitubulin activity and molecular modeling studies. Bioorganic & Medicinal Chemistry. 18: 2375-2387, 2010.
• Cimbora-Zovko T., Fritz G., Mikac N., Osmak M. Downregulation of RhoB GTPase confers resistance to cisplatin in human laryngeal carcinoma cells. Cancer Letters.  295:182-190, 2010.

2008-2009

• Brozović A., Damrot J., Tsaryk R., Helbig L., Nikolova T., Hartig C., Osmak M., Roos W., Kaina B., Fritz G. Cisplatin sensitivity is related to late DNA damage processing and checkpoint control rather than to the early DNA damage response. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 670, 1-2; 32-41, 2009.
• Majhen D., Nemet J., Richardson J., Gabrilovac J., Hajsig M., Osmak M., Eloit M., Ambriović-Ristov A. Differential role of αvβ3 and αvβ5 integrins in internalization and transduction efficacies of wild type and RGD4C fiber-modified adenoviruses. Virus Research. 139(1): 64-73, 2009.
• Brozović A., Majhen D, Roje V., Mikac N., Jakopec S., Fritz G., Osmak M., Ambriović-Ristov A. αvβ3 integrin mediated drug resistance in human laryngeal carcinoma cells is caused by glutathione dependent elimination of drug induced reactive oxidative species. Molecular Pharmacology. 74: 298-306, 2008.

2006-2007

• Brozović A., Osmak M. Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Letters. 251 (2007), 1; 1-16, 2007.
• Čimbora-Zovko T., Ambriović-Ristov A.; Lončarek J., Osmak M.: Altered cell-cell adhesion in cisplatin-resistant human carcinoma cells: A link between b-catenin/plakoglobin ratio and cisplatin resistance. European Journal of Pharmacology. 558: 27-36, 2007.
• Zisowsky J., Koegel S., Leyers S., Devarakonda K., Kassack M., Osmak M., Jaehde U. Relevance of drug uptake and efflux for platinum sensitivity of tumour cells. Biochemical Pharmacology. 73, 2; 298-307, 2007.
• Jakopec S., Dubravčić K., Polanc S., Košmrlj J., Osmak M.: Diazene JK-274 induces apoptosis-like cell death in human cervical carcinoma cells. Toxicology In Vitro. 20:217-226, 2006.
• Majhen D., Ambriović-Ristov, A. Adenoviral vectors-how to use them in cancer gene therapy, Virus Research. 119: 121-133, 2006.
• Majhen D., Gabrilovac J., Eloit M., Richardson J., Ambriović-Ristov A. Disulfide bond formation in NGR fiber-modified adenovirus is essential for retargeting to aminopeptidase N. Biochemical and Biophysical Research Communications. 348: 278-287, 2006.