PARP inhibitor cyanine dye conjugate with enhanced cytotoxic and antiproliferative activity in patient derived glioblastoma cell lines |
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| Institution: | 1. Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;2. Department of Pharmacology & The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;3. Neurosurgical Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;4. Department of Neurosurgery, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand;5. Department of Anatomical Pathology, LabPlus, Auckland City Hospital, 2 Park Road, Auckland, New Zealand;1. Department of Biological Sciences and Bioinformatics, Myongji University, Yongin-si, Gyunggi-do 17058, Republic of Korea;2. Department of Oriental Medicine Resources and Institute for Traditional Korean Medicine Industry, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea;1. Medicinal Chemistry, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;2. Pre-Pivotal Drug Product, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;3. Pharmicokinetics and Drug Metabolism, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;4. Neuroscience Research, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;5. Molecular Engineering, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;1. Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain;2. Dipartimento di Scienza e Tecnologia del Farmaco and Interdepartmental Centre, “Nanostructured Interfaces and Surfaces” – NIS, University of Turin, Via P. Giuria, 9, 10125 Turin, Italy;1. Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;2. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA;3. Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA 90095, USA;4. Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612, USA;5. Chemical Biology Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;6. Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;7. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;8. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;1. Department of Chemistry, Georgia State University, United States;2. Center for Diagnostics and Therapeutics, Petit Science Center, 100 Piedmont Ave SE, Atlanta, GA 30303, United States |
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| Abstract: | We describe the synthesis and in vitro activity of drug-dye conjugate 1, which is a combination of the PARP inhibitor rucaparib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed strong cytotoxic activity with nanomolar potency (EC50: 128 nM), which was a 780 fold improvement over rucaparib itself. We also observe a synergistic effect of 1 with temozolomide (TMZ), the standard drug for treatment for glioblastoma even though these cell lines were resistant to TMZ treatment. We envisage such conjugates to be worth exploring for their utility in the treatment of various brain cancers. |
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| Keywords: | Glioblastoma Temozolomide PARP inhibitors Rucaparib Heptamethine cyanine dyes |
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