RESEARCH PAPER Therapeutic Effects of AICAR and DOX Conjugated Multifunctional Nanoparticles in Sensitization and Elimination of Cancer Cells via Survivin Targeting Cenk Daglioglu 1,2 & Burcu Okutucu 2 Received: 14 June 2016 /Accepted: 14 October 2016 # Springer Science+Business Media New York 2016 ABSTRACT Purpose 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 re- ported on producing multifunctional nanoparticles (Fe 3 O 4 @SiO 2 (FITC)-FA/AICAR/DOX) aiming to over- come chemoresistance with synergetic effect of AICAR and DOX. In the present study, we demonstrated that these nano- particles not only show enhanced cellular uptake and cytotox- ic 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). Methods 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 ap- plicability of this approach in a variety of cancer types confirming the potential widespread utility of this approach. Results 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 molecular- ly targeted therapy and chemotherapeutic agent has the abil- ity to retain and enhance therapeutic efficacy. Conclusion Fe 3 O 4 @SiO 2 (FITC)-FA/AICAR/DOX nano- particles 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. KEY WORDS AICAR . chemoresistance . DOX . multifunctional nanoparticles . survivin ABBREVIATIONS 7-ADD 7-aminoactinomycin AICAR 5-aminoimidazole-4-carboxamide-1-β-D- ribofuranoside APTES 3-aminopropyltriethoxysilane DMEM Dulbecco’s modified Eagle medium DOX Doxorubicin FA Folic acid FACS Fluorescence-activated cell sorting FBS Fetal bovine serum FITC Fluorescein isothiocyanate Hsp90 Heat shock protein 90 IAPs Inhibitors of apoptosis proteins PBS Phosphate buffered saline PE-annexin-V Phycoerythrin-annexin-V PI Propidium iodide RPMI-1640 Roswell Park Memorial Institute- 1640 medium INTRODUCTION A characteristic feature of human cancers is the lack of a proper apoptotic response upon treatment with chemothera- peutic agents (1). Therefore, evasion of apoptosis constitutes a critical cause of drug resistance that frequently occurs in var- ious human cancers. Cancer cells are typically subject to a fairly small number of antiapoptotic proteins for their survival, * Cenk Daglioglu cenkdaglioglu@iyte.edu.tr 1 Faculty of Science, Department of Molecular Biology and Genetics, Izmir Institute of Technology, Urla/Izmir 35430, Turkey 2 Faculty of Science, Biochemistry Department, Ege University, Bornova/ Izmir 35040, Turkey Pharm Res DOI 10.1007/s11095-016-2053-7