Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study.

Autor: Sankaranarayanan RA; Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany., Peil J; Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany., Vogg ATJ; Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany., Bolm C; Institute of Organic Chemistry, RWTH Aachen University, 52056 Aachen, Germany., Terhorst S; Institute of Organic Chemistry, RWTH Aachen University, 52056 Aachen, Germany., Classen A; Institute of Organic Chemistry, RWTH Aachen University, 52056 Aachen, Germany., Bauwens M; Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany.; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+), 6229HX Maastricht, The Netherlands.; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229HX Maastricht, The Netherlands., Maurer J; Department of Molecular Gynecology, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany., Mottaghy F; Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany.; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+), 6229HX Maastricht, The Netherlands., Morgenroth A; Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Jan 04; Vol. 14 (1). Date of Electronic Publication: 2022 Jan 04.
DOI: 10.3390/cancers14010230
Abstrakt: PARP1 inhibitors (PARPi) are currently approved for BRCA mut metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [ 125 I] coupled olaparib derivative: [ 125 I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCA wt/mut ). Anchorage independent growth potential was evaluated using soft agar assay. [ 125 I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [ 125 I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCA wt cell lines. The clonogenic survival was significantly reduced after treatment with [ 125 I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [ 125 I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje