Your browser doesn't support javascript.
loading
Lumefantrine, an antimalarial drug, reverses radiation and temozolomide resistance in glioblastoma.
Rajesh, Yetirajam; Biswas, Angana; Kumar, Utkarsh; Banerjee, Indranil; Das, Subhayan; Maji, Santanu; Das, Swadesh K; Emdad, Luni; Cavenee, Webster K; Mandal, Mahitosh; Fisher, Paul B.
Afiliação
  • Rajesh Y; School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India.
  • Biswas A; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Kumar U; School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India.
  • Banerjee I; Department of Biotechnology, Indian Institute of Technology, Kharagpur, West Bengal 721302 India.
  • Das S; School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India.
  • Maji S; School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India.
  • Das SK; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Emdad L; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Cavenee WK; Virginia Commonwealth University (VCU) Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Mandal M; VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Fisher PB; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
Proc Natl Acad Sci U S A ; 117(22): 12324-12331, 2020 06 02.
Article em En | MEDLINE | ID: mdl-32409605
Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioblastoma / Antineoplásicos Alquilantes / Temozolomida / Lumefantrina / Antimaláricos Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioblastoma / Antineoplásicos Alquilantes / Temozolomida / Lumefantrina / Antimaláricos Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article