Surmeli Z.Gursoy P.Erdogan A.P.Bozkurt E.Atmaca H.Uzunoglu S.Sezgin C.Şanlı U.A.Uslu R.Karaca B.2024-07-222024-07-22201610104283http://akademikarsiv.cbu.edu.tr:4000/handle/123456789/15947The aim of this study was to investigate the cytotoxic and apoptotic effects of zoledronic acid (ZA) in combination with serine/threonine protein phosphatase inhibitors, calyculin-A (CA) and okadaic acid (OA), in human MCF-7 and MDA-MB-231 breast cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. DNA fragmentation and caspase-3/7 activity assays were performed to evaluate apoptosis. Activities of phosphatase 1 (PP1) and phosphatase 2A (PP2A) were measured by serine/threonine phosphatase ELISA kit. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2, p-Bcl-2, Bad, and p-Bad proteins were evaluated by Western blot analysis. Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis as compared to any agent alone in both MCF-7 and MDA-MB-231 breast cancer cells. Combination treatment also resulted in inhibition of both PP1 and PP2A activities. Both agents used alone or in combination did not induce significant changes in total PI3K, Akt, Bcl-2, and Bad expressions, while p-PI3K, p-Akt, p-Bcl-2, and p-Bad levels were reduced by the combination treatment as compared to agents alone. Moreover, apoptotic effect of combination treatment was significantly inhibited in the presence of LY294002, a specific PI3K inhibitor, in both breast cancer cell lines. In conclusion, synergistic apoptotic effect of the combination treatment is correlated with the block of the PI3K/Akt signal pathway in breast cancer cells. © 2015, International Society of Oncology and BioMarkers (ISOBM).EnglishApoptosisBlotting, WesternBreast NeoplasmsCell Line, TumorCell SurvivalDiphosphonatesDose-Response Relationship, DrugDrug SynergismEnzyme InhibitorsFemaleHumansImidazolesMCF-7 CellsOkadaic AcidOxazolesPhosphatidylinositol 3-KinasesPhosphoprotein PhosphatasesProto-Oncogene Proteins c-aktSignal Transduction2 morpholino 8 phenylchromonecalyculin Acaspase 3caspase 7okadaic acidphosphatasephosphatase 1phosphatase 2Aphosphatidylinositol 3 kinaseprotein BADprotein bcl 2protein kinase Bunclassified drugzoledronic acidbisphosphonic acid derivativecalyculin Aenzyme inhibitorimidazole derivativeokadaic acidoxazole derivativephosphatidylinositol 3 kinasephosphoprotein phosphataseprotein kinase Bzoledronic acidapoptosisArticlebreast cancer cell linecancer combination chemotherapycell viability assayconcentration responsecontrolled studyDNA fragmentationdrug cytotoxicitydrug potentiationenzyme activityenzyme inhibitionenzyme linked immunosorbent assayenzyme phosphorylationhumanhuman cellmonotherapypriority journalprotein expressionprotein phosphorylationsignal transductionWestern blottingantagonists and inhibitorsapoptosisbreast tumorcell survivaldose responsedrug effectsdrug potentiationfemaleMCF-7 cell linemetabolismpathologytumor cell lineArticle10.1007/s13277-015-3265-x