Die anti-tumorale Wirkung des neuen Phosphoinositid-3-Kinase-Inhibitors BAY 80-6946 auf humane Myelom-Zellen

The anti-tumour activity of the novel PI3K inhibitor BAY 80-6946 on myeloma cells

by Janina Hensen
Doctoral thesis
Date of Examination:2015-01-20
Date of issue:2015-01-12
Advisor:Prof. Dr. Margarete Schön
Referee:Prof. Dr. Michael P. Schön
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Martin Oppermann
Persistent Address: http://dx.doi.org/10.53846/goediss-4848

 

 

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Abstract

English

Overcoming drug resistance in the bone marrow microenvironment is an unresolved challenge in therapy of multiple myeloma. Despite numerous therapeutic approaches with new agents targeting the bone marrow microenvironment multiple myeloma still remains an incurable condition. Multiple myeloma cells exhibit numerous mechanisms of drug resistance. Constitutive activation of the Phosphatidylinositol-3-kinase (PI3K) is associated with tumour progression in multiple myeloma. Targeting the PI3K/Akt pathway can induce apoptosis in multiple myeloma cells. Therefore the use of PI3K inhibitors is predicted to increase the susceptibility of myeloma cells to anticancer therapy. We investigated the novel selective PI3K inhibitor BAY 80-6946 in four human myeloma cell lines. BAY 80-6946 induced significant inhibition of Akt phosphorylation in a dose-dependent manner being accompanied with an increase of apoptosis and inhibition of cell cycle progression. Moreover BAY 80-6946 could overcome the stimulation conferred by insulin-like growth-factor-1 (IGF-1). In addition, BAY 80-6946 showed in vivo activity against two human myeloma cell lines in a preclinical murine Xenograft model.
Keywords: myeloma; chemoresistance; PI3 kinase
Schlagwörter: Multiples Myelom; Medikamentenresistenz; PI3-Kinase
 
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