title: Therapeutic Effects of AICAR and DOX Conjugated Multifunctional Nanoparticles in Sensitization and Elimination of Cancer Cells via Survivin Targeting.
abstract: Resistance to chemotherapy is one of the major problems facing current cancer research. Enhancing tumor cell response to anticancer agents increases chemotherapeutic effectiveness. We have recently addressed this issue and reported on producing multifunctional nanoparticles (Fe3O4@SiO2(FITC)-FA/AICAR/DOX) aiming to overcome chemoresistance with synergetic effect of AICAR and DOX. In the present study, we demonstrated that these nanoparticles not only show enhanced cellular uptake and cytotoxic effect but can also show enhanced pro-apoptotic and anti-proliferative effects in five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat and MIA PaCa-2).
  
  
  
  The nanoparticles were examined by using flow cytometric analyses of apoptosis and cell cycle. In addition, we performed caspase-3 activity assay, which supported our flow cytometric data. Furthermore, we demonstrated the applicability of this approach in a variety of cancer types confirming the potential widespread utility of this approach.
  
  
  
  With the concept of co-delivery of AICAR and DOX in the nanoparticle formulation, the use of AICAR against survivin (BIRC5) sensitized cancer cells to DOX chemotherapy which resulted in effective cancer cell elimination. These result showed that combination therapy involving both a molecularly targeted therapy and chemotherapeutic agent has the ability to retain and enhance therapeutic efficacy.
  
  
  
  Fe3O4@SiO2(FITC)-FA/AICAR/DOX nanoparticles is superior to monotherapy via the synergetic effect of AICAR and DOX and also the nanoparticle formulation could overcome issues of toxicity with targeted therapy while maintaining the potent anticancer effects of AICAR and DOX. Graphical Abstract Apoptosis analysis of A549 cells by flow cytometry-based PE-annexin-V / 7-ADD double staining treated with low-dose (10 μg/ml) concentration of (1) Fe3O4@SiO2(FITC)-FA (2) Fe3O4@SiO2(FITC)-FA/AICAR, (3) Fe3O4@SiO2(FITC)-FA/DOX or (4) Fe3O4@SiO2(FITC)-FA/AICAR/DOX nanoparticles. Viable cells labelled with PE-annexin-V(-)/7-ADD(-), early apoptotic cells labelled with PE-annexin-V(+)/7-ADD(-) and apoptotic cells labelled with PE-annexin-V(+)/ 7-ADD(+) in flow cytometric graphics.
authors: Faculty of Science, Department of Molecular Biology and Genetics, Izmir Institute of Technology, Urla/Izmir, 35430, Turkey. cenkdaglioglu@iyte.edu.tr.|Faculty of Science, Biochemistry Department, Ege University, Bornova/Izmir, 35040, Turkey. cenkdaglioglu@iyte.edu.tr.
authors: Cenk
authors: 0000-0002-3857-2317
authors: C
authors: Daglioglu
authors: Faculty of Science, Biochemistry Department, Ege University, Bornova/Izmir, 35040, Turkey.
authors: Burcu
authors: B
authors: Okutucu
mesh_terms: D000072283:A549 Cells; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage*; D005290:Ferric Compounds / Q000008:administration & dosage; D005492:Folic Acid / Q000008:administration & dosage; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D058990:Molecular Targeted Therapy / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage*; D012265:Ribonucleotides / Q000008:administration & dosage*; D012822:Silicon Dioxide / Q000008:administration & dosage; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D005290:Ferric Compounds; D051034:Inhibitor of Apoptosis Proteins; D012265:Ribonucleotides; D000077022:Survivin; C000499:ferric oxide; D000620:Aminoimidazole Carboxamide; D012822:Silicon Dioxide; D004317:Doxorubicin; D005492:Folic Acid; D053148:Caspase 3; C031143:AICA ribonucleotide
keywords: AICAR; DOX; chemoresistance; multifunctional nanoparticles; survivin