Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid

Antonis D. Tsiailanis, Alexander Renziehausen, Sofia Kiriakidi, Eirinaios I. Vrettos, Georgios S. Markopoulos, Nisar Sayyad, Baydaa Hirmiz, Marie-Isabel Aguilar, Mark P. Del Borgo, Evangelos Kolettas, Robert E. Widdop, Thomas Mavromoustakos, Tim Crook, Nelofer Syed, Andreas G. Tzakos

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT1R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM.

Original languageEnglish
Pages (from-to)391-402
Number of pages12
JournalFree Radical Biology and Medicine
Volume160
DOIs
Publication statusPublished - 20 Nov 2020

Keywords

  • Antioxidants
  • ATR
  • Glioblastoma multiforme (GBM)
  • Losartan
  • Quercetin
  • Reactive oxygen species (ROS)

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