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Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

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  • Tiago De Oliveira, University of Göttingen
  • ,
  • Tina Goldhardt, University of Göttingen
  • ,
  • Marcus Edelmann, University of Göttingen
  • ,
  • Torben Rogge, Institute of Organic and Biomolecular Chemistry
  • ,
  • Karsten Rauch, Institute of Organic and Biomolecular Chemistry
  • ,
  • Nikola Dobrinov Kyuchukov, University of Göttingen
  • ,
  • Kerstin Menck, University of Göttingen, University of Münster
  • ,
  • Annalen Bleckman, University of Göttingen, University of Münster
  • ,
  • Joanna Kalucka
  • Shawez Khan, Københavns Universitet
  • ,
  • Jochen Gaedcke, University of Göttingen
  • ,
  • Martin Haubrock, University of Göttingen
  • ,
  • Tim Beissbarth, University of Göttingen
  • ,
  • Hanibal Bohnenberger, University of Göttingen
  • ,
  • Mélanie Planque, KU Leuven
  • ,
  • Sarah Maria Fendt, KU Leuven
  • ,
  • Lutz Ackermann, Institute of Organic and Biomolecular Chemistry
  • ,
  • Michael Ghadimi, University of Göttingen
  • ,
  • Lena Christin Conradi, University of Göttingen

Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo-and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. Materials and Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.

OriginalsprogEngelsk
Artikelnummer1011
TidsskriftCancers
Vol/bind13
Nummer5
Antal sider24
ISSN2072-6694
DOI
StatusUdgivet - mar. 2021

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© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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Copyright 2021 Elsevier B.V., All rights reserved.

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